Methods and devices for minimally-invasive extraocular delivery of radiation and/or pharmaceutics to the posterior portion of the eye

ABSTRACT

Methods and devices for minimally-invasive delivery of radiation to the posterior portion of the eye including a cannula comprising a distal portion connected to a proximal portion and a means for advancing a radionuclide brachytherapy source (RBS) toward the tip of the distal portion; a method of introducing radiation to the human eye comprising inserting a cannula between the Tenon&#39;s capsule and the sclera of the human eye and emitting the radiation from the cannula on an outer surface of said sclera.

CROSS REFERENCE

This application is a non-provisional application which claims priorityto U.S. continuation-in-part Ser. No. 12/497,644 filed Jul. 3, 2009, andU.S. provisional Ser. No. 61/347,226 filed May 21, 2010, thespecification of which is incorporated herein by reference in itsentirety.

FIELD OF THE INVENTION

The present invention is directed to minimally-invasive methods anddevices for introducing radiation to the posterior portion of the eyefor treating and/or managing eye conditions including maculadegeneration.

BACKGROUND OF THE INVENTION

Several diseases and conditions of the posterior segment of the eyethreaten vision. Age related macular degeneration (ARMD), choroidalneovascularization (CNV), retinopathies (e.g., diabetic retinopathy,vitreoretinopathy), retinitis (e.g., cytomegalovirus (CMV) retinitis),uveitis, macular edema, and glaucoma are several examples.

Age related macular degeneration (ARMD) is the leading cause ofblindness in the elderly. ARMD attacks the center region of the retina(i.e., macula), responsible for detailed vision and damages it, makingreading, driving, recognizing faces and other detailed tasks difficultor impossible. Current estimates reveal that approximately forty percentof the population over age 75, and approximately twenty percent of thepopulation over age 60, suffer from some degree of macular degeneration.“Wet” or exudative ARMD is the type of ARMD that most often causesblindness. In wet ARMD, newly formed choroidal blood vessels (choroidalneovascularization (CNV)) leak fluid and cause progressive damage to theretina. About 200,000 new cases of Wet ARMD occur each year in theUnited States alone.

Brachytherapy is treatment of a region by placing radioactive isotopesin, on, or near it. Both malignant and benign conditions aresuccessfully treated with brachytherapy. Lesion location dictatestreatment technique. For the treatment of tumors or tumor beds in thebreast, tongue, abdomen, or muscle capsules, catheters are inserted intothe tissue (interstitial application). Radiation may be delivered byinserting strands of radioactive seeds into these catheters for apredetermined amount of time. Permanent implants are also possible. Forexample, in the treatment of prostate cancer, radioactive seeds areplaced directly into the prostate where they remain indefinitely.Restenosis of coronary arteries after stent implantation, anon-malignant condition, has been successfully treated by placing acatheter into the coronary artery, then inserting a radioactive sourceinto the catheter and holding it there for a predetermined time in orderto deliver a sufficient dose to the vessel wall. Beta emitters, such asphosphorus 32 (P-32) and strontium 90 (Sr-90), and gamma emitters, suchas iridium 192 (Ir-192), have been used. The Collaborative OcularMelanoma Study (COMS), a multicenter randomized trial sponsored by theNational Eye Institute and the National Cancer Institute demonstratedthe utility of brachytherapy for the treatment of ocular cancers and/ortumors. The technique employs an invasive surgical procedure to allowplacement of a surface applicator (called an episcleral plaque) that isapplied extraocullarly by suturing it to the sclera. The gold plaquecontains an inner mold into which radioactive iodine 125 (I-125) seedsare inserted. The gold plaque serves to shield the tissues external tothe eye while exposing the sclera, choroid, choroidal melanoma, andoverlying retina to radiation. The plaque remains fixed for a few daysto one week in order to deliver approximately 85 Gy to the tumor apex.

Radiotherapy has long been used to treat arteriovenous malformations(AVM), a benign condition involving pathological vessel formation, inthe brain. An AVM is a congenital vascular pathology characterized bytangles of veins and arteries. The dose applicable to the treatment ofneovascularization in age-related macular degeneration (WAMD) by thedevices described herein may be based on stereotactic radiosurgery (SRS)treatment of arteriovenous malformations (AVM). SRS is used to deliverradiation to the AVM in order to obliterate it, and radiation is highlyeffective for AVM treatment. The minimum dose needed to obliterate anAVM with high probability is approximately 20 Gy. However, small AVMs(<1 cm) are often treated with a higher dose (e.g., 30 Gy) because whentreating small AVMs, a significant amount of eloquent brain (e.g., brainregions wherein injury typically causes disabling neurological deficits)is not exposed to the high dose of radiation. The reported SRS dosescorrespond to the dose received at the periphery of the AVM, while thedose at the nidus (center) may be up to a factor of 2.5 times greaterthan the reported SRS dose.

The vascular region involved in WAMD is much smaller than even thesmallest AVM, thus the effective doses are expected to be similar to thehighest doses used for AVM. Studies of irradiation of WAMD have shownthat greater than Gy are required, although one study indicates someresponse at 16 Gy. Without wishing to limit the present invention to anytheory or mechanism, the devices described herein for WAMD are expectedto be effective by delivering a nearly uniform dose to the entire regionof neovascularization or by delivering a nonuniform dose which may varyby a factor of 2.5 higher in the center as compared to the boundary ofthe region with minimum doses of 20 Gy and maximum doses of 75 Gy. Areport using radiosurgery for macular degeneration describes that a doseof only Gy was not effective (Haas et al, J Neurosurgery 93, 172-76,2000). In that study, the stated dose is the peripheral dose with thecenter being about 10% greater. Furthermore, the study results wereseverely plagued by retinal complications.

Without wishing to limit the present invention to any theory ormechanism, it is believed that the devices of the present invention areadvantageous over the prior art. For example, since SRS employs externalphoton beams which easily penetrate the ocular structures and passthrough the entire brain, the patient must be positioned such that thebeams may be directed towards the macula, making the geometricuncertainties of delivery a few millimeters. The devices of the presentinvention have geometric and dosimetric advantages because they may beplaced at the macula with submillimeter accuracy, and the betaradioisotope may be used to construct the radiation source withpredominately limited range.

The present invention features methods and devices forminimally-invasive delivery of radiation to the posterior portion of theeye.

SUMMARY OF THE INVENTION

The present invention features a method of irradiating a target of aneye in a patient. The method comprises inserting a cannula into apotential space under the Tenon's capsule. The cannula comprises aradionuclide brachytherapy source (RBS) at a treatment position, wherebythe RBS is positioned over the target as shown, for example, in FIG. 5.The RBS irradiates the target. In some embodiments, the treatmentposition is a location on or within the cannula (e.g., the middle of thecannula, along the length or a portion of the length of the cannula,near the end of the cannula). In some embodiments, the treatmentposition comprises a window on the cannula. In some embodiments, thetreatment position is configured to receive an RBS. In some embodiments,an indentation tip and/or a light source is disposed at the treatmentposition.

In some embodiments, the Tenon's capsule guides the insertion of thecannula and provides positioning support for the cannula. In someembodiments, the target is a lesion associated with the retina. In someembodiments, the target is located on the vitreous side of the eye. Insome embodiments, the target (e.g., lesion) is a benign growth or amalignant growth.

In some embodiments, method comprises inserting a cannula between theTenon's capsule and the sclera of the eye, for example at the limbus, apoint posterior to the limbus of the eye, a point between the limbus andthe formix. In some embodiments, any appropriate cannula may be used inaccordance with the present invention for the subtenon procedure. Insome embodiments, cannulas that may be used in accordance with thepresent invention include flexible cannulas, fixed shape cannulas (or acombination of a flexible and fixed shape cannula), and cannulas whichare tapered to provide a larger circumferential surface in the portionof the cannula which remains in the Tenon's capsule upon insertion,thereby providing additional positioning support to maintain the cannulaover the target. In some embodiments, the arc length of the distalportion of the cannula is suitably of sufficient length to penetrate theTenon's capsule and extend around the outside of the globe of the eye toa distal end position in close proximity to the macular target.

In some embodiments, the cannula employed in the inventive subtenonprocedure comprises a distal portion, which is a portion of the cannulathat is placed around a portion of the globe of the eye. The cannula hasa radionuclide brachytherapy source (“RBS”) at a treatment position(e.g., in the middle of the cannula, near the end, in the middle, alongthe length of the cannula). The cannula may be “preloaded” with an RBSor “afterloaded”. For example, in some embodiments, the RBS is loadedinto the cannula before the cannula is inserted. For example, in U.S.Pat. No. 7,070,554 to White, the brachytherapy device comprises a“preloaded” radiation source, i.e., a radiation source affixed at thetip of the device prior to the insertion of the device into the eye. Insome embodiments, the RBS is loaded into the cannula after the cannulais inserted. For example, see FIG. 6, where the radiation source isloaded to near the tip after the cannula has been inserted into the eye.Also, for example, see FIGS. 1C and 1D where the radiation source isadvanced from the handle/pig after positioning the distal portion. Themethod further comprises positioning the RBS over the sclera portionthat corresponds with the target (e.g., lesion), and the RBS irradiatesthe target (e.g., lesion) through the sclera.

The cannula may be of various shapes and sizes and constructed from avariety of materials. In some embodiments, the cannula is a fixed shapecannula. In some embodiments, the cannula is a flexible cannula,including an endoscope-like device. In some embodiments, the cannula istapered (e.g., a larger circumferential area in the portion whichremains in the Tenon's capsule upon insertion.

In some embodiments, the target is a lesion associated with the retina.In some embodiments, the target (e.g., lesion) is a neovascular lesion.

Neovascular lesions of wet macula degeneration generally cannot be seenvia indirect/direct ophthalmoscopy. In some embodiments, an angiogram(or other localizing technology such as optical coherence tomography,ultrasound) is performed, for example before the cannula is insertedbetween the Tenon's capsule and sclera. The angiogram may help locatethe cannula and the target (e.g., lesion), and direct the cannula to thecorrect position over the target. For example, while localizing thetarget (e.g., lesion) via the surrounding landmarks and in reference tothe previously obtained angiogram, the cannula may be directed to aprecise position. In some embodiments, the cannula comprises a windowand/or an orifice, and the window/orifice of the cannula can be placeddirectly behind the target (e.g., lesion). In some embodiments, aphotograph or video may be taken during the procedure to document theplacement of the cannula.

In some embodiments, an angiogram, optical coherence tomography,ultrasound, or other localizing technology is performed, for exampleafter the cannula is inserted between the Tenon's capsule and sclera.The localizing technology (e.g., angiogram) may help locate the cannulaand the target (e.g., lesion), and direct the cannula to the correctposition over the target. For example, while visualizing the target(e.g., lesion) via the localizing technology (e.g., angiogram), thecannula may be directed to a precise position. In some embodiments, thecannula comprises a window and/or an orifice, and the window/orifice ofthe cannula can be placed directly behind the target (e.g., lesion). Insome embodiments, the localizing technology (e.g., angiogram) is areal-time procedure. In some embodiments, localizing technology isoptical coherence tomography or ultrasound or other technology. In someembodiments, a photograph or video may be taken during the procedure todocument the placement of the cannula.

The RBS can be constructed to provide any dose rate to the target. Insome embodiments, the RBS provides a dose rate of between about 0.1 to 1Gy/min, between about 1 to 10 Gy/min, between about 10 to 20 Gy/min,between about 20 to Gy/min, between about 30 to 40 Gy/min, between about40 to 50 Gy/min, between about 50 to 60 Gy/min, between about 60 to 70Gy/min, between about 70 to 80 Gy/min, between about 80 to 90 Gy/min,between about 90 to 100 Gy/min, or greater than 100 Gy/min to the target(e.g., lesion).

The present invention also features a method of irradiating a target(e.g., lesion associated with the retina) of an eye in a patient. Themethod comprises inserting a cannula into the potential space under theTenon's capsule (e.g., between the Tenon's capsule and the sclera) ofthe eye. In some embodiments, the cannula is inserted at the limbus, apoint posterior to the limbus, or a point between the limbus and theformix. In some embodiments, the cannula comprises a distal portion(e.g., a portion of the cannula that is placed over a portion of theglobe of the eye). In some embodiments, the distal portion of thecannula is placed on or near the sclera behind the target (e.g., alesion on the retina). A radionuclide brachytherapy source (RBS) isadvanced through the cannula, for example to the treatment position(e.g., in the middle of the cannula, near a tip/end of distal portion),via a means for advancing the RBS. (In some embodiments, the means foradvancing the RBS comprises a guide wire. In some embodiments, the meansfor advancing the RBS comprises a ribbon). The target is exposed to theRBS. The RBS may be loaded before the cannula is inserted or after thecannula is inserted.

The cannula may be constructed in various shapes and sizes. In someembodiments, the distal portion is designed for placement around aportion of the globe of the eye. In some embodiments, the distal portionhas a radius of curvature between about 9 to 15 mm and an arc lengthbetween about 25 to 35 mm. In some embodiments, the cannula furthercomprises a proximal portion having a radius of curvature between aboutthe inner cross-sectional radius of the cannula and about 1 meter. Insome embodiments, the cannula further comprises an inflection point,which is where the distal portion and the proximal portions connect witheach other. In some embodiments, the angle θ₁ between the line l₃tangent to the globe of the eye at the inflection point and the proximalportion is between greater than about 0 degrees to about 180 degrees.

The present invention also features a hollow cannula with a fixed shape.The cannula comprises a distal portion for placement around a portion ofthe globe of an eye, wherein the distal portion has a radius ofcurvature between about 9 to 15 mm and an arc length between about 25 to35 mm. The cannula further comprises a proximal portion having a radiusof curvature between about the inner cross-sectional radius of thecannula and about 1 meter. The cannula further comprises an inflectionpoint, which is where the distal portion and the proximal portionsconnect with each other. In some embodiments, the angle θ₁ between theline l₃ tangent to the globe of the eye at the inflection point and theproximal portion is between greater than about 0 degrees to about 180degrees.

In some embodiments, once the distal end of the distal portion ispositioned within the vicinity of the target, the proximal portion iscurved away from the visual axis as to allow a user to have directvisual access in the eye.

The present invention also features a cannula with a fixed shape. Thecannula comprises a distal portion for placement around a portion of aglobe of an eye and a proximal portion connected to the distal portionvia an inflection point. In some embodiments, the distal portion has ashape of an arc formed from a connection between two points located onan ellipsoid, wherein the ellipsoid has an x-axis dimension “a”, ay-axis dimension “b,” and a z-axis dimension “c.” In some embodiments,“a” is between about 0 to 1 meter, “b” is between about 0 to 1 meter,and “c” is between about 0 to 1 meter. In some embodiments, the proximalportion has a shape of an arc formed from a connection between twopoints on an ellipsoid, wherein the ellipsoid has an x-axis dimension“d”, a y-axis dimension “e,” and a z-axis dimension “f.” In someembodiments, “d” is between about 0 to 1 meter, “e” is between about 0to 1 meter, and “f” is between about 0 to 1 meter. In some embodiments,the angle θ₁ between the line l₃ tangent to the globe of the eye at theinflection point and the proximal portion is between greater than about0 degrees to about 180 degrees.

The present invention further features a “fine positioning” surgicaltechnique. For example, after inserting a cannula into a potential spaceunder a Tenon's capsule of the eye of the patient, the surgeon observesthe position of (through the patient's pupil via a “visual axis”, seefor example FIG. 5) the treatment position of the cannula in a posteriorpole of the eye, and adjust it accordingly to accurately localize itover the target as shown in FIG. 5. In some embodiments, the physicianobserves the position of the treatment position and adjusts it while thepatient's eye is in a primary gaze position. A primary gaze position iswhen the patient looks straight ahead. In some embodiments, thephysician observes the position of the treatment position and adjusts itwhile the patient's eye is in any one of the following position:elevated, depressed, adducted, elevated and adducted, elevated andabducted, depressed and adducted, and depressed and abducted. By seeingthe position of the treatment position, the surgeon can adjust thecannula to position the treatment position over a target, as shown forexample in FIG. 5. In some embodiments, one of the advantages of thepresent “fine positioning” technique is that it allows for convenientand accurate placement of the RBS at the appropriate location behind theeye. In some embodiments, the fine positioning technique allows forplacement of the cannula with millimetric precision.

In some embodiments, the inventive methods of the present invention canbe performed under general or local anesthesia (e.g., retro- orperibulbar) to the eye. When a general or local anesthesia isadministered to the patient's eye, the eye will be in a primaryposition, and the patient has no motor movement of the eye. Accordingly,after the general or local anesthesia, the patient's eye will be in aprimary gaze position, i.e., looking straight forward. The presentinventive surgical methods and device allow for the surgeon toadminister the radiation accurately to the target in the eye while theeye is in a primary gaze position. In some embodiments, the advantage ofbeing able to perform the treatment while the patient's eye is in aprimary gaze position is that it does not require the surgeon to performadditional surgical steps to secure the eye to a non-primary gazeposition, as such securing steps may traumatize the eye.

The present invention also features a method of delivering radiation toan eye. The method comprises irradiating a target (e.g., a lesionassociated with the retina, a target on the vitreous side of the eye, abenign growth, a malignant growth) from an outer surface of the sclera.In some embodiments, the target receives a dose rate of greater thanabout 10 Gy/min.

The present invention also features a method of irradiating a target(e.g., a target/lesion associated with the retina) of an eye in apatient. The method comprises placing a radionuclide brachytherapysource (RBS) at or near a portion of the eye (e.g., sclera) thatcorresponds with the target. The RBS irradiates the target through thesclera, wherein more than 1% of the radiation from the RBS is depositedon a tissue at or beyond a distance of 1 cm from the RBS. In someembodiments, about 1% to 15% of the radiation from the RBS is depositedon a tissue or beyond a distance of 1 cm from the RBS. In someembodiments, about less than 99% of the radiation from the RBS isdeposited on a tissue at a distance less than 1 cm from the RBS.

The methods of the present invention also allow for delivering a smallervolume/area of radiation as compared to other procedures. For example, aradionuclide brachytherapy source (“RBS”) in the shape of a disk canprovide a controlled projection of radiation (e.g., a therapeutic dose)onto the target, while allowing for the radiation dose to fall offquickly at the periphery of the target. This keeps the radiation withina limited area/volume and may help prevent unwanted exposure ofstructures such as the optic nerve and/or the lens to radiation. Withoutwishing to limit the present invention to any theory or mechanism, it isbelieved that low areas/volumes of irradiation enables the use of higherdose rates, which in turn allows for faster surgery time and lesscomplications.

Any feature or combination of features described herein are includedwithin the scope of the present invention provided that the featuresincluded in any such combination are not mutually inconsistent as willbe apparent from the context, this specification, and the knowledge ofone of ordinary skill in the art. Additional advantages and aspects ofthe present invention are apparent in the following detailed descriptionand claims.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1A-1B shows views of various fixed shape cannula 100 according tothe present invention. FIG. 1A shows a side view of a fixed shapecannula 100 comprising a distal portion 110, a proximal portion 120, aninflection point 130, and a handle 140. Also shown is a tip 200, the arclength 185 of the distal portion 110, and the arc length 195 of theproximal portion 120. FIG. 1B shows a perspective view of the fixedshape cannula 100 from FIG. 1A. FIG. 1C shows the distal region 112 ofthe distal portion 110, the middle region 113 of the distal portion, awindow 510, a seed-shaped RBS 400, and a guide wire 350 having a distalend 320 wherein the wire 350 is housed in the handle 140 of the fixedshape cannula 100. FIG. 1D shows the guide wire 350 extended through theproximal portion 120 and the distal portion 110 of the fixed shapecannula 100. FIG. 1E shows the circle 181 defined by the curvature ofthe distal portion 110, the radius 182 of circle 181, and the radius ofcurvature 180 of the distal portion 110. FIG. 1F shows the circle 191defined by the curvature of the proximal portion 120, the radius 192 ofcircle 191, and the radius of curvature 190 of the proximal portion 120.

FIG. 2A-2M shows side views of various tips 200 of distal portions 110according to the present invention. Various tips 200 may comprise anorifice 500 or a window 510 and/or a light source 610, and/or anindentation tip 600. FIG. 2J illustrates a memory wire 300 wherein thememory wire 300 forms a flat spiral 310 when extended from the tip 200.FIG. 2K shows a distal chamber 210 wherein a memory wire 300 forms aflat spiral 310 when extended into the distal chamber 210.

FIG. 3 shows a side view of a distal portion 110 and a proximal portion120 according to the present invention.

FIG. 4A-4D shows perspective views of handles 140 according to thepresent invention. FIG. 4A shows a handle 140 comprising a thumb ring810, wherein the handle comprises a non-wire plunger 800. FIG. 4B showsa handle 140 comprising a graduated dial 820. FIG. 4C shows a handle 140comprising a slider 830. FIG. 4D shows an example of a fixed shapecannula comprising a radiation shielding pig 900 between the proximalportion 120 and the handle 140. A seed-shaped RBS 400 is attached to aguide wire 350, and the seed-shaped RBS 400 is housed within the pig900.

FIG. 5 shows the insertion of an assembled fixed shape cannula 100according to the present invention. The fixed shape cannula 100comprises a locator 160. The handle 140 and proximal portion 120 are outof the visual axis 220 of the physician and the patient. Tenon's capsulea layer of tissue running from the limbus anteriorly to the optic nerveposteriorly. The Tenon's capsule is surrounded anteriorly by the bulbarconjunctiva that originates at the limbus and reflects posteriorly intothe tarsal conjunctiva at the conjunctival formix.

FIG. 6A-6B shows the insertion of an unassembled fixed shape cannula 100according to the present invention, wherein the handle 140 and/orradiation shielding pig 900 is attached to the proximal portion 120 viaa connector 150 after the fixed shape cannula 100 is in place.

FIG. 7 shows an example of a radionuclide brachytherapy source (“RBS”)(e.g., seed-shaped RBS 400) inserted into a fixed shape cannula.

FIG. 8 shows lateral radiation dose profile of various devices,including that of the present device (SalutarisMD). The graph representsan example of relative radiation doses (y-axis) measured at distancesfrom the center of the target (x-axis). The SalutarisMD device presentsa more rapid decline in radiation dose as the distance away from thetarget periphery (e.g., area within about 1 mm from center of target)increases.

FIG. 9 shows a comparison of the insertion of a fixed shape cannula 100of the present invention (e.g., according to a posterior radiationapproach) to the insertion of a device used for an intravitrealradiation approach 910.

FIG. 10 is an illustration defining the term “lateral.” The drawing maybe representative of a horizontal cross-section of an eye ball, whereinthe target is the choroidal neovascular membrane (CNVM), the source isthe radioactive source (e.g., seed-shaped RBS 400), and the sclera islocated between the source and the target.

FIG. 11 shows an example of a radiation dose profile of a 1 mm Sr-90source as measured laterally at a 1.5 mm depth.

FIG. 12 shows an example of lines that are perpendicular to line l_(R)as viewed looking above the RBS/target downward along line IR.

FIG. 13 shows an example of an isodose (e.g., the area directlysurrounding the center of the target wherein the radiation dose issubstantially uniform), perpendicular to line l_(R), as viewed lookingabove the RBS/target downward along line l_(R). In this example, thearea wherein the radiation dose is substantially uniform extends up toabout 1.0 mm away from the center of the target.

FIG. 14A is a front cross sectional view of the distal portion 110 ofthe fixed shape cannula 100 wherein the top of the fixed shape cannula100 (e.g., distal portion 110) is rounded and the bottom is flat. FIG.14B is a bottom view of the distal portion 110 of FIG. 14A. FIG. 14C isa perspective view of an example of the RBS in the form of a disk 405having a height “h” 406 and a diameter “d” 407. FIG. 14D shows a varietyof side cross sectional views of RBSs having various shapes (e.g,rectangle, triangle, trapezoid). FIG. 14E shows an example of a RBScomprising a disk-shaped substrate 361. On the bottom surface 363 of thesubstrate 361 is an isotope 362. FIG. 14F shows examples of rotationallysymmetrical shapes. The present invention is not limited to the shapesshown in FIG. 14F. FIG. 14G shows an example of a radiation shaper 366comprising a window 364 (e.g., rotationally symmetrically-shapedwindow). The window 364 is generally radio-transparent and the radiationshaper 366 is generally radio-opaque. Radiation from a RBS issubstantially blocked or attenuated by the radiation shaper 366 but notthe window 364.

FIG. 15 shows an example of an ellipsoid 450 with an x-axis dimension, ay-axis dimension, and a z-axis dimension.

FIG. 16A shows a side view of the proximal portion 120 of the fixedshape cannula 100. FIG. 16B-D shows examples of inner diameters 171,outer diameters 172, and an inner radius 173 of a cross-section of theproximal portion 120 of the fixed shape cannula 100.

FIG. 17 shows an example of angle θ₁ 425 which is between line l₃ 420tangent to the globe of the eye at the inflection point 130 and theproximal portion 120.

FIG. 18A shows two different planes P₁ 431 and P₂ 432. FIG. 18B showsplane P₁ 431 as defined by the normal to the plane n₁ and plane P₂ 432defined by the normal to the plane n₂. FIG. 18C shows examples of anglesbetween P₁ 431 and P₂ 432.

FIG. 19A shows a perspective view of a fixed shape cannula 100 whereinthe cross section of the distal portion 110 and the proximal portion 120are generally circular.

FIG. 19B is a perspective view of a fixed shape cannula 100 wherein thecross section of the distal portion 110 and the proximal portion 120 isflattened in a ribbon-like configuration.

FIG. 20A shows a perspective view of a disk-shaped RBS inserted into ameans for advancing the RBS toward the tip 200 of the fixed shapecannula 100.

FIG. 20B is a perspective view of a plurality of cylindrical RBSsinserted into a means for advancing the RBS toward the tip 200 of thefixed shape cannula 100.

FIG. 21 shows a perspective view of a well having radio opaque walls,and a radionuclide brachytherapy source is set in the well.

FIG. 22 shows the radiation profiles where the intensity of theradiation at the edge falls off significantly, i.e., there is a fastfall of at the target edge. When a shielding is employed, the radiationfall off at the edge is faster compared to when there is no shielding.

FIG. 23 shows a side view of the handle. FIG. 23A shows an alternateside view of the handle.

FIG. 24 shows the insertion of the cannula into the eye. FIG. 24A showsa side view of a cannula.

FIG. 25 shows a perspective view of the present device.

FIG. 26 shows a table with combinations of dimensions for a, b and c.

FIG. 27 shows a table with combinations of dimensions for d, e and f.

FIG. 28 shows a table with a listing for non-limiting examples of suchSr-90-constructed radioactive seeds.

FIG. 29 shows a table with various relative radiation doses according todepth (distance away from source).

DESCRIPTION OF PREFERRED EMBODIMENTS

The present invention features methods and devices forminimally-invasive delivery of radiation to the posterior portion of theeye. Without wishing to limit the present invention to any theory ormechanism, it is believed that the sub-tenon method of deliveringradiation to the posterior portion of the eye of the present inventionis advantageous for several reasons. For example, the sub-tenonprocedure is minimally invasive and does not require extensive surgicaldissections. Thus, this unique procedure is faster, easier, and willpresent fewer side effects and/or complications the prior art methodsthat otherwise require dissections. Moreover, the sub-tenon method mayallow for simple office-based procedures with faster recovery times.

The sub-tenon method also allows for the tenon's capsule and otherstructures (e.g., sclera) to help guide and hold the device in placewhen in use. Keeping the cannula in a fixed location and at a distancefrom the target during the treatment reduces the likelihood of errorsand increases the predictability of dose delivery. In an intravitrealapproach (e.g., irradiating the target area by directing the radiationfrom within the vitreous chamber from anteriorly to the retina of theeye back towards the target), a physician is required to hold the devicein a fixed location and a fixed distance from the target in the spaciousvitreous chamber (see FIG. 9). It may be difficult for the physician tohold precisely that position for any length of time. Furthermore, it isgenerally not possible for the physician/surgeon to know the exactdistance between the probe and the retina; he/she can only estimate thedistance.

The methods of the present invention direct radiation from the posteriorside of the eye forwardly to a target; radiation is shielded in theback. Without wishing to limit the present invention to any theory ormechanism, it is believed that these methods will spare the patient fromreceiving ionizing radiation in the tissues behind the eye and deeperthan the eye. A pre-retinal approach (e.g., irradiating the target areaby directing the radiation from the anterior side of the retina backtoward the target) irradiates the anterior structures of the eye (e.g.,cornea, iris, ciliary body, lens) and has the potential to irradiate thetissues deeper than the lesion, such as the periorbital fat, bone, andthe brain. An intravitreal radiation approach also has the potential toirradiate the tissues deeper than the lesion (e.g., periorbital fat,bone, brain) and also, in a forward direction, the lens, ciliary bodyand cornea.

Prior to the present invention, radiotherapy as applied to the eyegenerally involves invasive eye surgeries. For example, an authoritativereport in the radiation therapy industry known as the “COMS study”discloses a protocol that employs an invasive surgical procedure todissect the periocular tissues and place the brachytherapy device. Thisis unlike the presently inventive minimally invasive subtenon method.

The prior art has disclosed a number of brachytherapy devices andmethods of using same for irradiating a lesion from behind the eye.However, these techniques do not employ the minimally invasive subtenonapproach of the present invention. Upon reading the disclosures of theprior art, one of ordinary skill would easily recognize that theprocedure being disclosed is quadrant dissection approach or aretro-bulbar intra-orbital approach, neither of which is the minimallyinvasive subtenon approach.

The following is a listing of numbers corresponding to a particularelement refer to herein:

-   -   100 fixed shape cannula    -   110 distal portion    -   112 distal region of distal portion    -   113 middle region of distal portion    -   120 proximal portion    -   130 inflection point    -   140 handle    -   150 connector    -   160 locator    -   171 inner diameter of cannula    -   172 outer diameter of cannula    -   173 inner radius of proximal portion    -   180 radius of curvature of distal portion    -   181 circle/oval defined by curve of distal portion    -   182 radius of circle/oval defined by curve of distal portion    -   185 arc length of distal portion    -   190 radius of curvature of proximal portion    -   191 circle/oval defined by curve of proximal portion    -   192 radius of circle/oval defined by curve of proximal portion    -   195 arc length of proximal portion    -   200 tip    -   210 distal chamber (disc-shaped)    -   220 visual axis of user    -   230 Tenon's capsule    -   235 sclera    -   300 memory wire    -   310 flat spiral    -   320 distal end of wire    -   350 guide wire    -   361 substrate    -   362 isotope (or “radionuclide”)    -   363 bottom surface of substrate    -   364 window of radiation shaper    -   366 radiation shaper    -   400 seed-shaped RBS    -   405 disk    -   406 height of disk    -   407 diameter of disk    -   410 radioactive source portion of wire    -   420 line l₃    -   425 angle θ₁    -   431 plane P₁    -   432 plane P₂    -   450 ellipsoid    -   500 orifice    -   510 window    -   520 distal edge of orifice/window    -   600 indentation tip    -   610 light source    -   800 non-wire plunger    -   810 thumb ring    -   820 graduated dial    -   830 slider    -   900 radiation shielding pig    -   910 device used for intravitreal radiation approach

As used herein, the term “about” means plus or minus 10% of thereferenced number. For example, an embodiment wherein an angle is about50 degrees includes an angle between 45 and 55 degrees.

The Eye

The mammalian eye is a generally spherical structure that performs itsvisual function by forming an image of an exterior illuminated object ona photosensitive tissue, the retina. The basic supporting structure forthe functional elements of the eye is the generally spherical tough,white outer shell, the sclera 235, which is comprised principally ofcollagenous connective tissue and is kept in its spherical shape by theinternal pressure of the eye. Externally the sclera 235 is surrounded bythe Tenon's capsule 230 (fascia bulbi), a thin layer of tissue runningfrom the limbus anteriorly to the optic nerve posteriorly. The Tenon'scapsule 230 is surrounded anteriorly by the bulbar conjunctiva, a thin,loose, vascularized lymphatic tissue that originates at the limbus andreflects posteriorly into the tarsal conjunctiva at the conjunctivalformix. Anteriorly the sclera 235 joins the cornea, a transparent, moreconvex structure. The point where the sclera and cornea is called thelimbus. The anterior portion of the sclera 235 supports and contains theelements that perform the function of focusing the incoming light, e.g.,the cornea and crystalline lens, and the function of regulating theintensity of the light entering the eye, e.g., the iris. The posteriorportion of the globe supports the retina and associated tissues.

In the posterior portion of the globe (referred to herein as the“posterior portion of the eye”) immediately adjacent the interiorsurface of the sclera 235 lays the choroid, a thin layer of pigmentedtissue liberally supplied with blood vessels. The portion of the choroidadjacent its interior surface is comprised of a network of capillaries,the choriocapillaris, which is of importance in the supply of oxygen andnutrients to the adjacent layers of the retina. Immediately anterior tothe choroid lies the retina, which is the innermost layer of theposterior segment of the eye and receives the image formed by therefractive elements in the anterior portion of the globe. Thephotoreceptive rod and cone cells of the retina are stimulated by lightfalling on them and pass their sensations via the retinal ganglion cellsto the brain. The central region of the retina is called “macula”; it isroughly delimited by the superior and inferior temporal branches of thecentral retina artery, it is mostly responsible for color vision,contrast sensitivity and shape recognition. The very central portion ofthe macula is called “fovea” and is responsible for fine visual acuity.

Novel Subtenon Approach to Introduce a Radionuclide Brachytherapy Source(“RBS”) to Posterior of Eye Globe

The present invention features a method of introducing radiation to theposterior portion of the eye in a minimally-invasive manner (byrespecting the intraocular space). Generally, the method comprisesirradiating from the outer surface of the sclera 235 to irradiate atarget. The target may be the macula, the retina, the sclera 235, and/orthe choroid. In some embodiments, the target may be on the vitreous sideof the eye. In some embodiments, the target is a neovascular lesion. Insome embodiments, the target receives a dose rate of radiation ofgreater than about 10 Gy/min.

In some embodiments, the method comprises using a hollow cannula 100 todeliver a RBS to the region of the sclera 235 corresponding to thetarget. (Although a cannula 100 of the present invention is used in thesubtenon approach, other instruments such as an endoscope may also beused in accordance with present novel subtenon approach). The cannula100 may be slid on the exterior curvature of the eye to reach theposterior portion of the eye. More specifically, in some embodiments,the method comprises introducing a cannula 100 comprising a RBS to theposterior portion of the eye between the Tenon's capsule 230 and thesclera 235 and exposing the posterior portion of the eye to theradiation. The cannula 100 may be inserted at a point posterior to thelimbus of the eye (e.g., any point between the limbus and theconjunctival formix).

The method may further comprise advancing a RBS through the cannula 100to the tip 200 of the distal portion 110 via a means for advancing theRBS.

In some embodiments, the method further comprises the step of exposingthe target (e.g., macula) of the eye to the radiation. In someembodiments, the method comprises targeting a neovascular growth in themacula.

In some embodiments, the RBS is placed in the subtenon space in closeproximity to the portion of the sclera 235 that overlays a portion ofchoroid and/or retina affected by an eye condition (e.g., WAMD, tumor).As used herein, a RBS that is placed “in close proximity” means that theRBS is about 0 mm to about 10 mm from the surface of the sclera 235. Insome embodiments, the radiation irradiates through the sclera 235 to thechoroid and/or retina.

In some embodiments, the step of inserting the cannula 100 between theTenon's capsule 230 and the sclera 235 further comprises inserting thecannula 100 into the superior temporal quadrant of the eye. In someembodiments, the step of inserting the cannula 100 between the Tenon'scapsule 230 and the sclera 235 further comprises inserting the cannula100 into the inferior temporal quadrant of the eye. In some embodiments,the step of inserting the cannula 100 between the Tenon's capsule 230and the sclera 235 further comprises inserting the cannula 100 into thesuperior nasal quadrant of the eye. In some embodiments, the step ofinserting the cannula 100 between the Tenon's capsule 230 and the sclera235 further comprises inserting the cannula 100 into the inferior nasalquadrant of the eye.

A RBS disposed at the distal end of a cannula 100 irradiates the target,and the target receives a dose rate of greater than about 10 Gy/min. Insome embodiments, the RBS provides a dose rate of greater than about 11Gy/min to the target. In some embodiments, the RBS provides a dose rateof greater than about 12 Gy/min to the target. In some embodiments, theRBS provides a dose rate of greater than about 13 Gy/min to the target.In some embodiments, the RBS provides a dose rate of greater than about14 Gy/min to the target. In some embodiments, the RBS provides a doserate of greater than about 15 Gy/min to the target. In some embodiments,the RBS provides a dose rate between about 10 to 15 Gy/min. In someembodiments, the RBS provides a dose rate between about 15 to 20 Gy/min.In some embodiments, the RBS provides a dose rate between about 20 to 30Gy/min. In some embodiments, the RBS provides a dose rate between about30 to Gy/min. In some embodiments, the RBS provides a dose rate betweenabout 40 to 50 Gy/min. In some embodiments, the RBS provides a dose ratebetween about 50 to 60 Gy/min. In some embodiments, the RBS provides adose rate between about 60 to 70 Gy/min. In some embodiments, the RBSprovides a dose rate between about 70 to 80 Gy/min. In some embodiments,the RBS provides a dose rate between about 80 to 90 Gy/min. In someembodiments, the RBS provides a dose rate between about 90 to 100Gy/min. In some embodiments, the RBS provides a dose rate of greaterthan 100 Gy/min.

In some embodiments, the distance from the RBS to the target is betweenabout 0.4 to 2.0 mm. In some embodiments, the distance from the RBS tothe target is between about 0.4 to 1.0 mm. In some embodiments, thedistance from the RBS to the target is between about 1.0 to 1.6 mm. Insome embodiments, the distance from the RBS to the target is betweenabout 1.6 to 2.0 mm.

In some embodiments, the RBS provides a dose rate between about 15 toGy/min to the target. In some embodiments, the RBS provides a dose ratebetween about 20 to 25 Gy/min to the target. In some embodiments, theRBS provides a dose rate between about 25 to 30 Gy/min to the target. Insome embodiments, the RBS provides a dose rate between about 30 to 35Gy/min to the target. In some embodiments, the RBS provides a dose ratebetween about 35 to 40 Gy/min to the target. In some embodiments, theRBS provides a dose rate between about 40 to 50 Gy/min to the target. Insome embodiments, the RBS provides a dose rate between about 50 to 60Gy/min to the target. In some embodiments, the RBS provides a dose ratebetween about 60 to 70 Gy/min to the target. In some embodiments, theRBS provides a dose rate between about 70 to 80 Gy/min to the target. Insome embodiments, the RBS provides a dose rate between about 80 to 90Gy/min to the target. In some embodiments, the RBS provides a dose ratebetween about 90 to 100 Gy/min to the target. In some embodiments, theRBS provides a dose rate greater than about 100 Gy/min to the target.

The present methods may be effective for treating and/or managing acondition (e.g., an eye condition). For example, the present methods maybe used to treat and/or manage wet (neovascular) age-related maculadegeneration. The present methods are not limited to treating and/ormanaging wet (neovascular) age-related macular degeneration. Forexample, the present methods may also be used to treat and/or manageconditions including macula degeneration, abnormal cell proliferation,choroidal neovascularization, retinopathy (e.g., diabetic retinopathy,vitreoretinopathy), macular edema, and tumors (e.g., intra ocularmelanoma, retinoblastoma).

Advantages of Subtenon Procedure

Without wishing to limit the present invention to any theory ormechanism, it is believed that the novel subtenon methods of the presentinvention are advantageous over the prior art because they are lessinvasive (e.g., they do not invade the intraocular space), they requireonly local anesthesia, and they provide a quicker patient recovery time.For example, the technique of introducing radiation to the posteriorportion of the eye by suturing a radioactive plaque on the sclera 235 atthe posterior portion of the eye requires a 360° peritomy (e.g.,dissection of the conjunctiva), isolation of the four recti muscles andextensive manipulation of the globe. Furthermore, when the plaque isleft in place and then removed a few days later, a second surgery isrequired. The methods of the present invention are easier to perform.Also, the intraocular method of exposing the posterior pole of the eyeto radiation involves performing a vitrectomy as well as positioning andholding the radioactive probe in the preretinal vitreous cavity for asignificant length of time without a stabilizing mechanism. Thistechnique is difficult to perform, requires a violation of theintraocular space, and is prone to a number of possible complicationssuch as the risk of retinal detachment, cataracts, glaucoma, and/orendophthalmitis. Because of the complexity of this technique, afellowship in vitreoretina surgery is required. The methods of thepresent invention are easier to perform, minimally-invasive, and do notimpose a risk of damage to the intraocular structures. Moreover, themethods of the present invention do not require additional vitreoretinafellowship training as these methods can be employed by any surgicalophthalmologist.

As used herein, the term “minimally-invasive” method means a method thatdoes not require that an instrument be introduced into the intraocularspace (anterior, posterior, or vitreous chamber) of the eye for deliveryof a radioactive source to the posterior portion of the eye or a methodthat does not require the suturing of a radioactive plaque on the sclera235 or extensive conjunctiva peritomy. For example, theminimally-invasive methods of the present invention only require a smallincision of conjunctiva and Tenon's capsule 230 for inserting of acannula 100 comprising a RBS to the posterior portion of the eye. Thepreferred approach is through the superotemporal quadrant, howeverentrance through the supero nasal, the inferotemporal or the inferonasalquandrant can be employed.

The present invention features a method of introducing radiation to ahuman eye comprising the steps of inserting a cannula 100 between theTenon's capsule 230 and the sclera 235 of the human eye at a pointposterior to the limbus of the human eye; wherein the cannula 100comprises a distal portion 110 having a radius of curvature 180 betweenabout 9 to 15 mm and an arc length 185 between about 25 to 35 mm; aproximal portion 120; and a means for advancing a RBS toward the tip 200of the cannula 100 (e.g., tip 200 of distal portion 110); placing thedistal portion 110 on or near the sclera 235 behind a neovascularlesion; advancing the RBS to the tip 200 of the distal end 110; andexposing the neovascular lesion to the RBS.

In some embodiments, the area of sclera 235 exposed to the radiation isabout 0.1 mm to about 0.5 mm in diameter. In some embodiments, the areaof sclera 235 exposed to the radiation is about 0.5 mm to about 2 mm indiameter. In some embodiments, the area of sclera 235 exposed to theradiation is about 2 mm to 3 mm in diameter. In some embodiments, thearea of sclera 235 exposed to the radiation is about 3 mm to 5 mm indiameter. In some embodiments, the area of sclera 235 exposed to theradiation is about 5 mm to 10 mm in diameter. In some embodiments, thearea of sclera 235 exposed to the radiation is about 10 mm to 25 mm indiameter.

The Cannula

The present invention features a fixed shape cannula 100 for deliveringa RBS to the back of the eye. The fixed shape cannula 100 has a defined,fixed shape and comprises a distal portion 110 connected to a proximalportion 120 via an inflection point 130. The distal portion 110 of thefixed shape cannula 100 is for placement around a portion of the globeof the eye. In some embodiments, the distal portion 110 of the fixedshape cannula 100 is inserted below the Tenon capsule 230 and above thesclera 235. In some embodiments, the fixed shape cannula 100 is hollow.

As used herein, a fixed shape cannula 100 having a “fixed” shape refersto a fixed shape cannula 100 that has a single permanent shape andcannot be manipulated into another shape. For example, the fixed shapecannula 100 of the present invention has a “fixed” shape because itgenerally has one shape, whereas an endoscope does not have a “fixed”shape because it is flexible and can be manipulated into another shape.A fixed shape cannula 100 having a “fixed” shape may also be constructedfrom a material that has some flexibility. Accordingly, when a pressureis applied onto the fixed shape cannula 100 of the present invention itmay bend. However, when the pressure is removed, the fixed shape cannula100 of the present invention may resume its original fixed shape orretain a portion of the deformation shape.

In some embodiments, an inflection point 130 may be defined as a pointon a curve in which the sign or direction of the curvature changes. Insome embodiments, there may be a straight portion of the fixed shapecannula between the distal portion and proximal portion. Accordingly, insome embodiments, the proximal and distal portions are separated at aninflection point where the curvature changes sign. In some embodiments,the proximal portion ends at a point where the curvature changes from afinite value to zero.

In some embodiments, the inflection point 130 helps to bend the proximalportion 120 of the fixed shape cannula 100 away from the visual axis 220of the subject (e.g., patient) and of the user (e.g., physician) whoinserts the fixed shape cannula 100 into a subject. In some embodiments,the user may visualize the posterior portion of the eye of the subjectby employing a coaxial ophthalmoscopic device such as an indirectophthalmoscope or a surgical microscope while the fixed shape cannula100 is in place.

Distal Portion Dimensions Of The Fixed shape cannula

The dimensions of the globe of the eye are fairly constant in adults,usually varying by no more than about 1 mm in various studies. However,in hyperopia and myopia, the anteroposterior diameter of the globe mayvary significantly from the normal measurement.

The outer anteroposterior diameter of the globe ranges between about21.7 mm to 28.75 mm with an average of about 24.15 mm (radius rangesfrom about 10.8 mm to 14.4 mm with an average of about 12.1 mm) inemmetropic eyes, whereas the internal anteroposterior diameter averagesabout 22.12 mm (radius averages about 11.1 mm). In high hypermetropiaand myopia, the anteroposterior diameter is frequently as low as about20 mm and as high as about 29 mm or more, respectively.

The transverse diameter (e.g., the diameter of the globe at the anatomicequator measured from the nasal to the temporal side) averages about23.48 mm (radius averages about 11.75 mm), and the vertical diameter(e.g., the diameter of the globe at the anatomic equator measuredsuperiorly to inferiorly) averages about 23.48 mm (radius averages about11.75 mm). The circumference of the globe at the anatomic equatoraverages about 74.91 mm. The volume of the globe of the eye averagesbetween about 6.5 mL to 7.2 mL, and has a surface area of about 22.86cm².

The distal portion 110 of the fixed shape cannula 100 may be designed ina number of ways. In some embodiments, the distal portion 110 of thefixed shape cannula 100 has an arc length 185 between about 25 to 35 mm.

In some embodiments, the arc length 185 of the distal portion 110 (e.g.,length of the arc 111 of the distal portion 110) may be of variouslengths. For example, hyperopic or pediatric patients may have smallereyes and may require a smaller arc length 185 of the distal portion 110.Or, for example, different insertion points (e.g., limbus, conjunctivalformix) of the fixed shape cannula 100 may require different arc lengths185 of the distal portion 110. In some embodiments, the arc length 185of the distal portion 110 may be between about 10 mm to about 15 mm. Insome embodiments, the arc length 185 of the distal portion 110 may bebetween about 15 mm to about 20 mm. In some embodiments, the arc length185 of the distal portion 110 may be between about 20 mm to about 25 mm.In some embodiments, the arc length 185 of the distal portion 110 may bebetween about 25 mm to about 30 mm. In some embodiments, the arc length185 of the distal portion 110 may be between about 30 mm to about 35 mm.In some embodiments, the arc length 185 of the distal portion 110 may bebetween about 35 mm to about 50 mm. In some embodiments, the arc length185 of the distal portion 110 may be between about 50 mm to about 75 mm.

As used herein, the term “arc length” 185 of the distal portion 110 ofthe fixed shape cannula refers to the arc length measured from the tip200 of the distal portion 110 to the inflection point 130. The term“radius of curvature” 180 of the distal portion 110 of the fixed shapecannula 100 refers to the length of the radius 182 of the circle/oval181 defined by the curve of the distal portion 110 (see FIG. 19A). Insome embodiments, the invention employs a unique sub-tenon insertionmethodology, wherein the arc length is designed to be of sufficientlength to traverse the Tenon's capsule and portion of the eye which isinterposed between the Tenon's capsule entry point and the target (e.g.,macula) area.

In some embodiments, the distal portion 110 of the fixed shape cannula100 has a radius of curvature 180 between about 9 to 15 mm. In someembodiments, the radius of curvature 180 of the distal portion 110 isbetween about 9 mm to about mm. In some embodiments, the radius ofcurvature 180 of the distal portion 110 is between about 10 mm to about11 mm. In some embodiments, the radius of curvature 180 of the distalportion 110 is between about 11 mm to about 12 mm. In some embodiments,the radius of curvature 180 of the distal portion 110 is between about12 mm to about 13 mm. In some embodiments, the radius of curvature 180of the distal portion 110 is between about 13 mm to about 14 mm. In someembodiments, the radius of curvature 180 of the distal portion 110 isbetween about 14 mm to 15 mm. In some embodiments, the arc length 185 ofthe distal portion 110 and the inflection point 130 may also serve tolimit the depth of insertion of the fixed shape cannula 100 along thesclera 235, preventing the tip 200 of the distal portion 110 fromaccidentally damaging posterior ciliary arteries or the optic nerve.

In some embodiments, the distal portion 110 has a radius of curvature180 substantially equal to the radius of curvature of the sclera 235 ofan adult human eye. Without wishing to limit the present invention toany theory or mechanism, it is believed that having the radius ofcurvature 180 of the distal portion 110 be substantially equal to theradius of curvature of the sclera 235 of an adult human eye isadvantageous because it will ensure that the area that is exposed to theradiation is the outer surface of the sclera 235, generally above themacula. In addition, the design permits accurate placement of the RBSand allows a user (e.g., a surgeon) to have the RBS remain fixed in thecorrect position with minimal effort during the application of theradiation dose. This enables improved geometric accuracy of dosedelivery and improved dosing.

In some embodiments, the radius of curvature 180 of the distal portion110 is constant. For example, the radius of curvature 180 in the distalportion 110 may be a constant 12 mm. In some embodiments, the radius ofcurvature 180 of the distal portion 110 is variable. For example, theradius of curvature 180 in the distal portion 110 may be larger at thedistal region 112 and smaller at the middle region 113.

Without wishing to limit the present invention to any theory ormechanism, it is believed that different and variable radii of curvaturemay provide for easier and more accurate positioning in special cases,such as that of a myopic eye in which the anteroposterior diameter isgreater than the vertical diameter. In this case, it may be advantageousto use a fixed shape cannula 100 having a distal portion 110 with anoverall larger radius of curvature 180 and specifically having arelatively shorter radius of curvature in the distal region 112 ascompared to the radius of curvature in the middle region 113. Similarly,it may be advantageous to use a fixed shape cannula 100 having a distalportion 110 with an overall smaller radius of curvature 180 andspecifically having a relatively larger radius of curvature in thedistal region 112 as compared to the radius of curvature in the middleregion 113.

The distal portion 110 and the proximal portion 120 of the fixed shapecannula 100 each have an inner diameter 171 and outer diameter 172 ofthe respective vertical cross sections. As shown in FIG. 16, in someembodiments, the inner diameter 171 of the vertical cross section of thedistal portion 110 is constant (e.g., the inside of the fixed shapecannula 100 has a circular cross section). In some embodiments, theinner diameter 171 of the vertical cross section of the distal portion110 is variable (e.g., the inside of the fixed shape cannula 100 has anoval cross section). In some embodiments, the outer diameter 172 ofvertical cross section of the distal portion 110 is constant (e.g., theoutside of the fixed shape cannula 100 has a circular cross section). Insome embodiments, the outer diameter 172 of the vertical cross sectionof the distal portion 110 is variable (e.g., the outside of the fixedshape cannula 100 has an oval cross section).

In some embodiments, the fixed shape cannula 100 has an outer crosssectional shape that is generally circular. In some embodiments, thefixed shape cannula 100 has an outer cross sectional shape that isgenerally round. In some embodiments, the fixed shape cannula 100 has anouter cross sectional shape that is oval, rectangular, egg-shaped, ortrapezoidal.

In some embodiments, the fixed shape cannula 100 has an internal crosssectional shape that is configured to allow a RBS to be passed through.

In some embodiments, the fixed shape cannula 100 has an internal crosssectional shape that is generally circular. In some embodiments, thefixed shape cannula 100 has an outer cross sectional shape that isgenerally round. In some embodiments, the fixed shape cannula 100 has aninner cross sectional shape that is oval, rectangular, egg-shaped, ortrapezoidal.

In some embodiments, the average outer diameter 172 of the verticalcross section of the distal portion 110 is between about 0.1 mm and 0.4mm. In some embodiments, the average outer diameter 172 of the distalportion 110 is between about 0.4 mm and 1.0 mm. In some embodiments, theaverage outer diameter 172 of the distal portion 110 is about 0.9 mm. Insome embodiments, the average outer diameter 172 of the distal portion110 is between about 1.0 mm and 2.0 mm. In some embodiments, the averageouter diameter 172 of the distal portion 110 is between about 2.0 mm and5.0 mm. In some embodiments, the average outer diameter 172 of thedistal portion 110 is between about 5.0 mm and 10.0 mm.

In some embodiments, the average inner diameter 171 of the verticalcross section of the distal portion 110 is between about 0.1 mm and 0.4mm. In some embodiments, the average inner diameter 171 of the distalportion 110 is between about 0.4 mm and 1.0 mm. In some embodiments, theaverage inner diameter 171 of the distal portion 110 is about 0.9 mm. Insome embodiments, the average inner diameter 171 of the distal portion110 is between about 1.0 mm and 2.0 mm. In some embodiments, the averageinner diameter 171 of the distal portion 110 is between about 2.0 mm and5.0 mm. In some embodiments, the average inner diameter 171 of thedistal portion 110 is between about 5.0 mm and 10.0 mm.

In some embodiments, the average outer diameter 172 of the verticalcross section of the distal portion 110 is about 0.4 mm and the averageinner diameter 171 of the vertical cross section of the distal portion110 is about 0.1 mm (e.g., the wall thickness is about 0.15 mm). In someembodiments, the average outer diameter 172 of the vertical crosssection of the distal portion 110 is about 0.7 mm and the average innerdiameter 171 of the vertical cross section of the distal portion 110 isabout 0.4 mm (e.g., the wall thickness is about 0.15 mm). In someembodiments, the average outer diameter 172 of the distal portion 110 isabout 0.9 mm and the average inner diameter 171 of the distal portion110 is about 0.6 mm (e.g., the wall thickness is about 0.15 mm). In someembodiments, the average outer diameter 172 of the distal portion 110 isabout 1.3 mm and the average inner diameter 171 of the distal portion isabout 0.8 mm (e.g., the wall thickness is about 0.25 mm). In someembodiments, the average outer diameter 172 of the distal portion 110 isabout 1.7 mm and the average inner diameter 171 of the distal portion110 is about 1.2 mm (e.g., the wall thickness is about 0.25 mm). In someembodiments, the average outer diameter 172 of the distal portion 110 isabout 1.8 mm and the average inner diameter 171 of the distal portion110 is about 1.4 mm (e.g., the wall thickness is about 0.20 mm). In someembodiments, the average outer diameter 172 of the distal portion 110 isabout 2.1 mm and the average inner diameter 171 of the distal portion isabout 1.6 mm (e.g., the wall thickness is about 0.25 mm).

In some embodiments, the diameter of the distal portion 110 is between a12 gauge and 22 gauge wire needle size.

In some embodiments, the thickness of the distal portion wall (e.g., asmeasured between the inner diameter 171 of the distal portion 110 andthe outer diameter 172 of the distal portion 110) is between about 0.01mm to about 0.1 mm. In some embodiments, the thickness of the distalportion wall (e.g., as measured between the inner diameter 171 of thedistal portion 110 and the outer diameter 172 of the distal portion 110)is between about 0.1 mm to about 0.3 mm. In some embodiments, thethickness of the distal portion wall is between about 0.3 mm to about1.0 mm. In some embodiments, the thickness of the distal portion wall isbetween about 1.0 mm to about 5.0 mm. In some embodiments, the thicknessof the distal portion wall is constant along the length of the distalportion 110. As shown in FIG. 16B, in some embodiments, the thickness ofthe distal portion wall is constant about the inner diameter 171 andouter diameter 172. In some embodiments, the thickness of the distalportion wall varies throughout the distal portion 110, for example alongthe length of the distal portion 110. As shown in FIGS. 16C and 16D, insome embodiments, the thickness of the distal portion wall varies aboutthe inner diameter 171 and outer diameter 172.

Proximal Portion Dimensions of the Fixed Shape Cannula

The proximal portion 120 of the fixed shape cannula 100 may also bedesigned in a number of ways. In some embodiments, the proximal portion120 of the fixed shape cannula 100 has an arc length 195 between about10 to 75 mm.

The arc length 195 of the proximal portion 120 (e.g., length of the arcof the proximal portion 120) may be of various lengths. In someembodiments, the arc length 195 of the proximal portion 120 may bebetween about 10 mm to about 15 mm. In some embodiments, the arc length195 of the proximal portion 120 may be between about 15 mm to about 18mm. In some embodiments, the arc length 195 of the proximal portion 120may be between about 18 mm to about 25 mm. In some embodiments, the arclength 195 of the proximal portion 120 may be between about 25 mm toabout 50 mm. In some embodiments, the arc length 195 of the proximalportion 120 may be between about 50 mm to about 75 mm.

As used herein, the term “arc length” 195 of the proximal portion 120 ofthe fixed shape cannula 100 refers to the arc length measured from theinflection point 130 to the opposite end of the proximal portion 120.The term “radius of curvature” 190 of the proximal portion 120 of thefixed shape cannula 100 refers to the length of the radius 192 of thecircle/oval 191 defined by the curve of the proximal portion 120 (seeFIG. 19B).

In some embodiments, the proximal portion 120 of the fixed shape cannula100 has a radius of curvature 190 between about an inner radius 173 ofthe proximal portion 120 of the fixed shape cannula 100, for examplebetween 0.1 mm to 1 meter. In some embodiments, the radius of curvature190 of the proximal portion 120 is constant. In some embodiments, theradius of curvature 190 of the proximal portion 120 is variable.

The distal portion 110 and the proximal portion 120 of the fixed shapecannula 100 each have an inner diameter 171 and outer diameter 172 ofthe respective vertical cross sections. As shown in FIG. 16, in someembodiments, the inner diameter 171 of the vertical cross section of theproximal portion 120 is constant (e.g., the inside of the fixed shapecannula 100 has a circular cross section). In some embodiments, theinner diameter 171 of the vertical cross section of the proximal portion120 is variable (e.g., the inside of the fixed shape cannula 100 has anoval cross section). In some embodiments, the outer diameter 172 ofvertical cross section of the proximal portion 120 is constant (e.g.,the outside of the fixed shape cannula 100 has a circular crosssection). In some embodiments, the outer diameter 172 of the verticalcross section of the proximal portion 120 is variable (e.g., the outsideof the fixed shape cannula 100 has an oval cross section).

In some embodiments, the fixed shape cannula 100 has an outer crosssectional shape that is generally round. In some embodiments, the fixedshape cannula 100 has an outer cross sectional shape that is oval,rectangular, egg-shaped, or trapezoidal.

In some embodiments, the fixed shape cannula 100 has an internal crosssectional shape that is configured to allow a RBS to be passed through.

In some embodiments, the fixed shape cannula 100 has an internal crosssectional shape that is generally round. In some embodiments, the fixedshape cannula 100 has an inner cross sectional shape that is oval,rectangular, egg-shaped, or trapezoidal.

As shown in FIG. 17, line l₃ 420 represents the line tangent to theglobe of the eye at the inflection point 130 and/or limbus. Line l₃ 420and line l₄ (the straight portion of the fixed shape cannula 100 or aline parallel to the straight portion of the fixed shape cannula 100)form angle θ₁ 425 (see FIG. 17). The fixed shape cannula 100 may beconstructed in many ways, therefore angle θ₁ 425 may have variousvalues. In some embodiments, the angle θ₁ 425 is between greater thanabout 0 to 180 degrees. In some embodiments, if the fixed shape cannula100 bends through a larger angle, the value of angle θ₁ 425 is greater.

In some embodiments, angle θ₁ 425 is between about 1 to 10 degrees. Insome embodiments, angle θ₁ 425 is between about 10 to 20 degrees. Insome embodiments, angle θ₁ 425 is between about 20 to 30 degrees. Insome embodiments, angle θ₁ 425 is between about 30 to 40 degrees. Insome embodiments, angle θ₁ 425 is between about 40 to 50 degrees. Insome embodiments, angle θ₁ 425 is between about 50 to 60 degrees. Insome embodiments, angle θ₁ 425 is between about 60 to 70 degrees. Insome embodiments, angle θ₁ 425 is between about 70 to 80 degrees. Insome embodiments, angle θ₁ 425 is between about 80 to 90 degrees.

In some embodiments, angle θ₁ 425 is between about 90 to 100 degrees. Insome embodiments, angle θ₁ 425 is between about 100 to 110 degrees. Insome embodiments, angle θ₁ 425 is between about 110 to 120 degrees. Insome embodiments, angle θ₁ 425 is between about 120 to 130 degrees. Insome embodiments, angle θ₁ 425 is between about 140 to 150 degrees. Insome embodiments, angle θ₁ 425 is between about 150 to 160 degrees. Insome embodiments, angle θ₁ 425 is between about 160 to 170 degrees. Insome embodiments, angle θ₁ 425 is between about 170 to 180 degrees.

As shown in FIG. 1, FIG. 3, and FIG. 5, in some embodiments, the distalportion 110 and the proximal portion 120 lie in the same plane. In someembodiments, the proximal portion 120 is off at an angle from the distalportion 110, for example the proximal portion 120 is rotated or twistedwith respect to the distal portion 110 such that the distal portion 110and the proximal portion 120 lie in different planes. As shown in FIGS.18A and 18B, in some embodiments, the distal portion 110 lies in planeP₁ 431 and the proximal portion 120 lies in plane P₂ 432. Plane P₁ 431and plane P₂ 432 can be defined by their respective normal lines, forexample n₁ for plane P₁ 431 and n₂ for plane P₂ 432. Given that thedistal portion 110 can be represented as n₁ and the proximal portion 120can be represented as n₂, in some embodiments, the distal portion 110and proximal portion 120 can be rotated/twisted with respect to eachother between about −90° and +90^(°). FIG. 18C illustrates severalexamples of spatial relationships between the proximal portion 120 P₂432 and distal portion 110 P₁ 431. The spatial relationships between theproximal portion 120 and distal portion 110 are not limited to theexamples in FIG. 18.

In some embodiments, the region around the inflection point 130 is agently curving bend such that a radiation source (e.g., a disk-shaped405 RBS, a seed-shaped 400 RBS) may be pushed through the fixed shapecannula 100 (e.g., from the proximal portion 120 to the distal portion110).

In some embodiments, the inflection point 130 of the fixed shape cannula100 extends into a segment of straight fixed shape cannula between thedistal portion 110 and the proximal portion 120. In some embodiments,the segment is between about 0 to 2 mm. In some embodiments, the segmentis between about 2 to 5 mm. In some embodiments, the segment is betweenabout 5 to 7 mm. In some embodiments, the segment is between about 7 to10 mm. In some embodiments, the segment is more than about 10 mm.

The present invention also features a fixed shape cannula 100 with afixed shape comprising a distal portion 110, a proximal portion 120, andan inflection point 130 connecting the distal portion 110 and theproximal portion 130, wherein the distal portion 110 and/or proximalportion 120 has a shape of an arc formed from a connection between afirst point and a second point located on an ellipsoid 450, theellipsoid 450 having an x-axis, a y-axis, and a z-axis (see FIG. 15).Ellipsoids can be defined by the equation below:

${\frac{x^{2}}{a^{2}} + \frac{y^{2}}{b^{2}} + \frac{z^{2}}{c^{2}}} = 1$

In some embodiments, the distal portion 110 has the shape of an arcderived from the ellipsoid 450 having the x-axis dimension “a,” they-axis dimension “b,” and the z-axis dimension “c.” In some embodiments,“a” is between about 0 to 1 meter, “b” is between about 0 to 1 meter,and “c” is between about 0 to 1 meter. For example, in some embodiments,“a” is between about 0 to 50 mm, “b” is between about 0 and 50 mm, and“c” is between about 0 and 50 mm.

In some embodiments, the ellipsoid 450 has a dimension “a”, “b”, and/or“c” between about 1 to 3 mm. In some embodiments, the ellipsoid 450 hasa dimension “a”, “b”, and/or “c” between about 3 to 5 mm. In someembodiments, the ellipsoid 450 has a dimension “a”, “b”, and/or “c”between about 5 to 8 mm. In some embodiments, the ellipsoid 450 has adimension “a”, “b”, and/or “c” between about 8 to 10 mm. In someembodiments, the ellipsoid 450 has a dimension “a”, “b”, and/or “c”between about 10 to 12 mm. In some embodiments, the ellipsoid 450 has adimension “a”, “b”, and/or “c” between about 12 to 15 mm. In someembodiments, the ellipsoid 450 has a dimension “a”, “b”, and/or “c”between about 15 to 18 mm. In some embodiments, the ellipsoid 450 has adimension “a”, “b”, and/or “c” between about 18 to 20 mm. In someembodiments, the ellipsoid 450 has a dimension “a”, “b”, and/or “c”between about 20 to 25 mm. In some embodiments, the ellipsoid 450 has adimension “a”, “b”, and/or “c” greater than about 25 mm.

In some embodiments, the ellipsoid 450 has dimensions “a” and “b” whichare both between about 9 and 15 mm, for example about 12.1 mm. Thisellipsoid 450 may be appropriate for designing a fixed shape cannula 100for an emmetropic eye, wherein the eye is generally spherical. In someembodiments, the ellipsoid 450 has a dimension “a” between about 11 mmand 17 mm, for example about 14 mm, and a dimension “b” between about 9mm and 15 mm, for example about 12.1 mm. This ellipsoid 450 may beappropriate for designing a fixed shape cannula 100 for a myopic eye,wherein the axial length is about 28 mm. In some embodiments, theellipsoid 450 has a dimension “a” between about 7 to 13 mm, for example10 mm, and a dimension “b” between about 9 to 15 mm, for example 12 mm.This ellipsoid 450 may be appropriate for a hyperopic eye, wherein theaxial length is about 20 mm.

In some embodiments, the proximal portion 120 has the shape of an arcderived from the ellipsoid 450 having the x-axis dimension “d,” they-axis dimension “e,” and the z-axis dimension “f.” In some embodiments,“d” is between about 0 to 1 meter, “e” is between about 0 to 1 meter,and “f” is between about 0 to 1 meter. In some embodiments, “d” isbetween about 0 to 50 mm, “e” is between about 0 and 50 mm, and “f” isbetween about 0 and 50 mm.

In some embodiments, the ellipsoid 450 has a dimension “d”, “e”, and/or“f” between about 1 to 3 mm. In some embodiments, the ellipsoid 450 hasa dimension “d”, “e”, and/or “f” between about 3 to 5 mm. In someembodiments, the ellipsoid 450 has a dimension “d”, “e”, and/or “f”between about 5 to 8 mm. In some embodiments, the ellipsoid 450 has adimension “d”, “e”, and/or “f” between about 8 to 10 mm. In someembodiments, the ellipsoid 450 has a dimension “d”, “e”, and/or “f”between about 10 to 12 mm. In some embodiments, the ellipsoid 450 has adimension “d”, “e”, and/or “f” between about 12 to 15 mm. In someembodiments, the ellipsoid 450 has a dimension “d”, “e”, and/or “f”between about 15 to 18 mm. In some embodiments, the ellipsoid 450 has adimension “d”, “e”, and/or “f” between about 18 to 20 mm. In someembodiments, the ellipsoid 450 has a dimension “d”, “e”, and/or “f”between about 20 to 25 mm. In some embodiments, the ellipsoid 450 has adimension “d”, “e”, and/or “f” between about 25 to 30 mm. In someembodiments, the ellipsoid 450 has a dimension “d”, “e”, and/or “f”between about 30 to 40 mm. In some embodiments, the ellipsoid 450 has adimension “d”, “e”, and/or “f” between about 40 to 50 mm. In someembodiments, the ellipsoid 450 has a dimension “d”, “e”, and/or “f”greater than about 50 mm.

The ellipsoid 450 may be a sphere, wherein “a” is equal to “b”, and “b”is equal to “c”. The ellipsoid 450 may be a scalene ellipsoid (e.g.,triaxial ellipsoid) wherein “a” is not equal to “b”, “b” is not equal to“c”, and “a” is not equal to “c”.

In some embodiments, the ellipsoid 450 is an oblate ellipsoid wherein“a” is equal to “b”, and both “a” and “b” are greater than “c”. In someembodiments, the ellipsoid 450 is a prolate ellipsoid wherein “a” isequal to “b”, and both “a” and “b” are less than “c”.

In some embodiments, “a” is about equal to “b” (e.g., for an emmetropiceye). In some embodiments, “a” is not equal to “b” (e.g., for anemmetropic eye). In some embodiments, “b” is about equal to “c”. In someembodiments, “b” is not equal to “c”. In some embodiments, “a” is aboutequal to “c”. In some embodiments, “a” is not equal to “c”. In someembodiments, “d” is about equal to “e”. In some embodiments, “d” is notequal to “e”. In some embodiments, “e” is about equal to “f”. In someembodiments, “e” is not equal to “f”. In some embodiments, “d” is aboutequal to “f”. In some embodiments, “d” is not equal to “f”.

The dimensions of “a,” “b,” and “c” may vary. In FIG. 26, Table 1 listsseveral combinations of dimensions. The dimensions of “a,” “b,” and “c”are not limited to those listed in Table 1.

The dimensions of “d,” “e,” and “f” may vary. In FIG. 27, Table 2 listsseveral combinations of dimensions. The dimensions of “d,” “e,” and “f”are not limited to those listed in Table 2.

In some embodiments, the ellipsoid 450 is egg-shaped or a variationthereof.

The present invention also features a hollow fixed shape cannula 100with a fixed shape comprising a distal portion 110 for placement arounda portion of a globe of an eye, wherein the distal portion 110 has aradius of curvature 180 between about 9 to 15 mm and an arc length 185between about 25 to 35 mm. The fixed shape cannula 100 comprises aproximal portion 120 having a radius of curvature 190 between about aninner cross-sectional radius 173 of the fixed shape cannula 100 (e.g.,proximal portion 120 of fixed shape cannula 100) and about 1 meter andan inflection point 130, which is where the distal portion 110 and theproximal portion 120 connect with each other. In some embodiments, oncethe distal end (e.g., tip 200, distal region 112) of the distal portion110 is positioned within the vicinity of the target, the proximalportion 120 is curved away from the visual axis 220 as to allow a user(e.g., physician) to have direct visual access in the eye.

In some embodiments, the present invention features a new cannula, saidnew cannula comprising: (a) a distal segment for placement around aportion of a globe of an eye; wherein the distal segment has a radius ofcurvature between about 9 to 15 mm and an arc length between about 25 to35 mm; (b) a proximal segment having a radius of curvature between aboutan inner cross-sectional radius of said new cannula and about 1 meter;and (c) an inflection point which is where the distal segment and theproximal segments connect with each other; wherein an angle θ₁ between aline l₃ tangent to the globe of the eye at the inflection point and theproximal segment is between greater than about 0 degrees to about 180degrees. In some embodiments, the proximal end of the distal segment ofsaid new cannula is tapered such the circumference of the proximal endis larger than the circumference of the distal end of the distalsegment. In some embodiments, the distal segment of said new cannula hasan arc length which is at least π/4 times the diameter of the globe ofthe eye under treatment. In some embodiments, the distal segment of saidnew cannula has sufficient arc length to penetrate the Tenon's capsuleof the eye being treated and to extend around the outer diameter of saideye such that the distal end of the distal segment is positioned in theproximity of, and behind, the macula. In some embodiments, there is ameans of advancing a RBS which is disposed within said new cannula andwherein said new cannula is for delivering the RBS to the back of theeye, said RBS having a rotationally symmetrical exposure surface capableof more than 1% of the total source radiation energy flux beyond adistance of 1 cm from the exposure surface.

Locator on the Cannula

In some embodiments, the cannula 100 comprises a locator 160. In someembodiments, a locator 160 is a physical mark (e.g., a visible markand/or a physical protrusion) disposed on the cannula 100. In someembodiments, the locator 160 is for aligning the cannula 100 tofacilitate the positioning of the distal portion 110 and/or tip 200and/or RBS. In some embodiments, the locator 160 is disposed on thecannula 100 such that it will align with the limbus when the cannula 100is in place (see for example FIG. 5, FIG. 6B). In some embodiments, theinflection point 130 located on cannula 100 may serve as a locator 160.For example, the user can position the inflection point 130 at thelimbus as an indication that the tip 200 of the cannula 100 isapproximately at the sclera 235 region that corresponds with the target,e.g., the macula.

Materials of Cannula

In some embodiments, the cannula 100 is constructed from a materialcomprising stainless steel, gold, platinum, titanium, the like, or acombination thereof. In some embodiments, the distal portion 110 and/orthe proximal portion 120 are constructed from a material comprisingsurgical stainless steel. In some embodiments, the distal portion 110and/or the proximal portion 120 are constructed from a materialcomprising other conventional materials such as Teflon, other metals,metal alloys, polyethylene, polypropylene, other conventional plastics,or combinations of the foregoing may also be used. For example, thedistal portion 110 may be constructed from a material comprising aplastic. As another example, a part of the tip of the distal portion 110may be constructed from a material comprising a plastic, and theremainder of the distal portion 110 and the proximal portion 120 may beconstructed from a material comprising a metal. Without wishing to limitthe present invention to any theory or mechanism, it is believed thatthe plastic has sufficient softness and/or flexibility to minimize thepossibility of penetration of the sclera 235 or the Tenon's capsule 230when the cannula 100 is inserted into the eye, as described herein. Inaddition, the length of the plastic portion of the distal portion 110,as well as the specific plastic, are preferably selected so that distalportion 110 maintains its radius of curvature 180 when the cannula 100is inserted into the eye.

Handle, Extruding/Advancing Mechanism, Guide Wire

In some embodiments, the cannula 100 is functionally connected with ahandle 140 (see FIG. 1, FIG. 4, FIG. 5). The handle 140 may be connectedto the proximal portion 120 of the cannula 100. In some embodiments, thecannula 100 is free of a proximal portion 120, and a handle 140 isattached to the distal portion 110 at around the location where theproximal portion 120 normally connects to the distal portion 110 (e.g.,the inflection point 130). Without wishing to limit the presentinvention to any theory or mechanism, it is believed that a handle 140may provide the user with a better grip on the cannula 100 and allow forthe user to more easily reach the posterior portion of the eye. In someembodiments, the handle 140 is attached to the cannula 100 by africtional fit and/or conventional fastening means. In some embodiments,the handle 140 comprises a radiation shielding material. In someembodiments, the cannula 100 and handle 140 are preassembled as onepiece. In some embodiments, the cannula 100 and handle 140 are assembledprior to inserting into the eye. In some embodiments, the cannula 100and handle 140 are assembled after inserting the cannula 100 intoposterior portion of the eye according to the present invention.

In some embodiments, the proximal portion 120 and/or handle 140 compriseone or more mechanisms for advancing the RBS (e.g., disk 405,seed-shaped RBS 400). Examples of such mechanisms include a slidemechanism, a dial mechanism, a thumb ring 810, a graduated dial 820, aslider 830, a fitting, a Toughy-Burst type fitting, the like, or acombination thereof (see FIG. 4).

In some embodiments, the cannula 100 further comprises a non-wireplunger 800 (see FIG. 4). Non-limiting examples of a non-wire plunger800 include a solid stick, a piston, or a shaft. In some embodiments,the non-wire plunger 800 is constructed from a material comprising aplastic, a metal, a wood, the like, or a combination thereof. In someembodiments, the RBS is extended from and retracted into the cannula 100with the non-wire plunger 800. In some embodiments, the non-wire plunger800 is air tight. In some embodiments, the non-wire plunger 800 is notair tight. In some embodiments, the cannula 100 further comprises aspring.

In some embodiments, the cannula 100 comprises a guide wire 350 and/or anon-wire plunger 800 which function to advance the RBS. In someembodiments, the guide wire 350 and the non-wire plunger 800 aresubstituted by another mechanism which functions to advance the RBS. Insome embodiments, the RBS may be advanced and retracted by hydrostaticpressure employing a fluid (e.g., a saline, an oil, or another type offluid) using a syringe or other method. In some embodiments, the RBS isadvanced and/or retracted by a pneumatic mechanism (e.g., air pressure)and retracted by a vacuum.

In some embodiments, the non-wire plunger 800 and/or the guide wire 350comprise stainless steel. In some embodiments, the non-wire plunger 800and/or the guide wire 350 are braided. In some embodiments, the guidewire 350 comprises a material that is the same material used to encasethe RBS (e.g., disk 405, seed-shaped RBS 400) such as gold, silverstainless steel, titanium, platinum, the like, or a combination thereof.In some embodiments, the guide wire 350 comprises a material that is thesame material that the radiation has been deposited into. In someembodiments, the RBS may be advanced and retracted by a Nitinol wire.

Orifice on the Cannula

In some embodiments, the cannula 100 comprises an orifice 500 located onan interior side (e.g., bottom) of the distal portion 110 (see FIG. 2).The orifice 500 may be for allowing the radiation to pass through thecannula 100 and reach the target. In some embodiments, the orifice 500may be located on the tip 200 of the distal portion 110 or on otherareas of the distal portion 110. In some embodiments, the distal portion110 may have multiple orifices 500. In some embodiments, the orifice 500has a round shape (e.g., circular). The orifice 500 may also havealternate shapes such as a square, an oval, a rectangle, an ellipse, ora triangle. In some embodiments, the orifice 500 has an area of about0.01 mm² to about 0.1 mm². In some embodiments, the orifice 500 has anarea of about 0.1 mm² to about 1.0 mm². In some embodiments, the orifice500 has an area of about 1.0 mm² to about 10.0 mm².

In some embodiments, the size of the orifice 500 is smaller than thesize of the RBS (e.g., disk 405, seed-shaped RBS 400). In someembodiments, the orifice 500 is circular and has a diameter of about 0.1millimeters. In some embodiments, the orifice 500 is circular and has adiameter between about 0.01 millimeters and about 0.1 millimeters. Insome embodiments, the orifice 500 is circular and has a diameter betweenabout 0.1 millimeters and 1.0 millimeters. In some embodiments, theorifice 500 is circular and has a diameter between about 1.0 millimetersand 5.0 millimeters. In some embodiments, the orifice 500 is circularand has a diameter between about 5.0 millimeters and 10.0 millimeters.

In some embodiments, the orifice 500 is rectangular. In someembodiments, the orifice 500 is rectangular and is about 1.0 mm by 2.5mm. In some embodiments, the orifice 500 is rectangular and is about 0.5mm by 2.5 mm. In some embodiments, the orifice 500 is rectangular and isabout 0.5 by 2.0 mm. In some embodiments, the orifice 500 is rectangularand is about 0.5 mm by 1.5 mm. In some embodiments, the orifice 500 isrectangular and is about 0.5 mm by 1.0 mm. In some embodiments, theorifice 500 is rectangular and is about 0.5 mm by 0.5 mm. In someembodiments, the orifice 500 is rectangular and is about 0.25 mm by 2.5mm. In some embodiments, the orifice 500 is rectangular and is about0.25 mm by 2.0 mm. In some embodiments, the orifice 500 is rectangularand is about 0.25 mm by 1.5 mm. In some embodiments, the orifice 500 isrectangular and is about 0.25 mm by 1.0 mm. In some embodiments, theorifice 500 is rectangular and is about 0.25 mm by 0.5 mm. In someembodiments, the orifice 500 is rectangular and is about 0.25 mm by 0.25mm.

In some embodiments, the distal edge 520 of the orifice 500 is locatedbetween about 0.1 mm and 0.5 mm from the tip 200 of the distal portion110. In some embodiments, the distal edge 520 of the orifice 500 islocated between about 0.5 mm and 1.0 mm from the tip 200 of the distalportion 110. In some embodiments, the distal edge 520 of the orifice 500is located between about 1.0 mm and 2.0 mm from the tip 200 of thedistal portion 110. In some embodiments, the distal edge 520 of theorifice 500 is located between about 2.0 mm and 5.0 mm from the tip 200of the distal portion 110. In some embodiments, the distal edge 520 ofthe orifice 500 is located between about 5.0 mm and 10.0 mm from the tip200 of the distal portion 110. In some embodiments, the distal edge 520of the orifice 500 is located between about 10.0 mm and 20.0 mm from thetip 200 of the distal portion 110.

Window on the Cannula

As used herein, the term “radiotransparent” refers to a material thatabsorbs less than about 10⁻¹ or less than about 10⁻² of the radiationflux. For example, a window 510 comprising a radiotransparent materialincludes a window 510 comprising a material that absorbs 10′ of theradiation flux.

In some embodiments, the cannula 100 comprises a window 510. In someembodiments, the cannula 100 comprises an orifice 500 and a window 510,both generally disposed at the distal portion 110 of the cannula 100(see FIG. 2). In some embodiments, the window 510 of the cannula 100comprises a material that allows for more radiation transmission thanother portions of the cannula 100. A window 510, for example, maycomprise a lower density material or comprise a material having a loweratomic number. In some embodiments, the window 510 may comprise the samematerial as the cannula 100 but have a smaller wall thickness. In someembodiments, the window 510 comprises a radiotransparent material. Insome embodiments, the window 510 comprises the same material as thecannula 100 and has the same wall thickness of the cannula 100. In someembodiments, the window 510 is the area of the cannula 100 from wherethe radiation is emitted.

In some embodiments, the cannula 100 comprises a window 510 located onan interior side (e.g., bottom) of the distal portion 110. The window510 may be used to allow the radiation to pass through the cannula 100and reach a target tissue. In some embodiments, the window 510 is aportion of the cannula 100 having a thickness that is less than thethickness of a cannula wall. In some embodiments, the window 510 is aportion of the cannula 100 having a thickness that is equal to thethickness of a cannula wall. In some embodiments, the window 510 is aportion of the cannula 100 having a thickness that is greater than thethickness of a cannula wall.

In some embodiments, the distal portion 110 may have multiple windows510. In some embodiments, the window 510 has a round shape (e.g.,circular). The window 510 may also have alternate shapes such as asquare, an oval, a rectangle, or a triangle. In some embodiments, thewindow 510 has an area of about 0.01 mm² to about 0.1 mm². In someembodiments, the window 510 has an area of about 0.1 mm² to about 1.0mm². In some embodiments, the window 510 has an area of about 1.0 mm² toabout 10.0 mm². In some embodiments, the window 510 has an area of about2.5 mm². In some embodiments, the window 510 has an area of greater than2.5 mm², for example 50 mm² or 100 mm².

In some embodiments, the window 510 is rectangular. In some embodiments,the window 510 is rectangular and is about 1.0 mm by 2.5 mm. In someembodiments, the window 510 is rectangular and is about 0.5 mm by 2.5mm. In some embodiments, the window 510 is rectangular and is about 0.5by 2.0 mm. In some embodiments, the window 510 is rectangular and isabout 0.5 by 1.5 mm. In some embodiments, the window 510 is rectangularand is about 0.5 by 1.0 mm. In some embodiments, the window 510 isrectangular and is about 0.5 mm by 0.5 mm. In some embodiments, thewindow 510 is rectangular and is about 0.25 mm by 2.5 mm. In someembodiments, the window 510 is rectangular and is about 0.25 mm by 2.0mm. In some embodiments, the window 510 is rectangular and is about 0.25mm by 1.5 mm. In some embodiments, the window 510 is rectangular and isabout 0.25 mm by 1.0 mm. In some embodiments, the window 510 isrectangular and is about 0.25 mm by 0.5 mm. In some embodiments, thewindow 510 is rectangular and is about 0.25 mm by 0.25 mm. In someembodiments, the window 510 has an area of greater than 2.5 mm², forexample, 50 mm², or 100 mm².

In some embodiments, the size of the window 510 is smaller than the sizeof the RBS (e.g., disk 405, seed-shaped RBS 400). In some embodiments,the size of the window 510 is larger than the size of the RBS. In someembodiments, the window 510 is elliptical and has axis dimensions ofabout 0.1 millimeters. In some embodiments, the window 510 is ellipticaland has axis dimensions between about 0.1 millimeters and 1.0millimeters. In some embodiments, the window 510 is elliptical and hasaxes dimensions between about 1.0 millimeters and 5.0 millimeters.

In some embodiments, the distal edge 520 of the window 510 is locatedbetween about 0.1 mm and 0.5 mm from the tip 200 of the distal portion110. In some embodiments, the distal edge 520 of the window 510 islocated between about 0.5 mm and 1.0 mm from the tip 200 of the distalportion 110. In some embodiments, the distal edge 520 of the window 510is located between about 1.0 mm and 2.0 mm from the tip 200 of thedistal portion 110. In some embodiments, the distal edge 520 of thewindow 510 is located between about 2.0 mm and 5.0 mm from the tip 200of the distal portion 110. In some embodiments, the distal edge 520 ofthe window 510 is located between about 5.0 mm and 10.0 mm from the tip200 of the distal portion 110. In some embodiments, the distal edge 520of the window 510 is located between about 10.0 mm and 20.0 mm from thetip 200 of the distal portion 110.

Radiation Shielding

In some embodiments, the handle 140 and/or the proximal portion 120and/or distal portion 110 of the cannula 100 is constructed from amaterial that can further shield the user from the RBS (e.g., disk 405).In some embodiments, the handle 140 and/or the proximal portion 120comprises a material that is denser than the cannula 100. In someembodiments, the handle 140 and/or proximal portion 120 comprises amaterial that is thicker than the cannula 100. In some embodiments, thehandle 140 and/or the proximal portion 120 comprise more layers ofmaterial than the cannula 100.

In some embodiments, a part of the distal portion 110 is constructedfrom a material that can further shield the user and/or the patient fromthe RBS. For example, the side of the distal portion 110 opposite theside that contacts the sclera 235 is constructed from a material thatcan further shield the patient from the RBS.

In some embodiments, the proximal portion 120 and/or the handle 140comprises a container that provides radiation shielding, herein referredto as a radiation shielding “pig” 900 (see FIG. 4, FIG. 6). Theradiation shielding pig 900 allows for the RBS (e.g., a disk 405, aseed-shaped RBS 400) to be stored in a retracted position. In someembodiments, the radiation shielding pig 900 provides for the storage ofthe RBS so that the device may be safely handled by the user.

In some embodiments, the proximal portion 120 and/or the handle 140 ofthe cannula 100 has a wall thickness designed to shield the RBS. In someembodiments, the proximal portion 120 and/or the handle 140 of thecannula 100 comprises stainless steel and has a thickness between about1 mm to about 2 mm. In some embodiments, the proximal portion 120 and/orthe handle 140 of the cannula 100 comprises stainless steel and has athickness between about 2 mm to about 3 mm. In some embodiments, theproximal portion 120 and/or the handle 140 of the cannula 100 comprisesstainless steel and has a thickness between about 3 mm to about 4 mm. Insome embodiments, the proximal portion 120 and/or the handle 140 of thecannula comprises stainless steel and has a thickness between about 4 mmto about 5 mm. In some embodiments, the proximal portion 120 and/or thehandle 140 of the cannula 100 comprises stainless steel and has athickness between about 5 mm to about 10 mm.

In some embodiments, the proximal portion 120 and/or the handle 140 ofthe cannula 100 comprises a plurality of layers. In some embodiments,the proximal portion 120 and/or the handle 140 comprises a plurality ofmaterials. In some embodiments, the plurality of materials comprises atungsten alloy. Tungsten alloys are well known to those skilled in theart. For example, in some embodiments, the tungsten alloy has a hightungsten content and a low amount of NiFe, as is sometimes used inradiation shielding.

In some embodiments, shielding a beta isotope in a RBS may be difficult.In some embodiments, a material having a low atomic number (Z) may beused for shielding (e.g., polymethyl methacrylate). In some embodiments,one or more layers of material are used for shielding, wherein an innerlayer comprises a material having a low atomic number (e.g., polymethylmethacrylate) and an outer layer comprises lead. In some embodiments,the proximal portion 120 and/or the handle 140 and/or the radiationshielding pig 900 comprises an inner layer surrounded by an outer layer.In some embodiments, the proximal portion 120 and/or the handle 140and/or the radiation shielding pig 900 comprises an inner layer ofpolymethyl methacrylate (or other material) surrounded by an outer layerof lead (or other material).

In some embodiments, the inner layer is between about 0.1 mm to 0.25 mm.In some embodiments, the inner layer is between about 0.25 mm to 0.50 mmthick. In some embodiments, the inner layer is between about 0.5 to 1.0mm thick. In some embodiments, the inner layer is between about 1.0 mmto 1.5 mm thick. In some embodiments, the inner layer is between about1.5 mm and 2.0 mm thick. In some embodiments, the inner layer is betweenabout 2.0 mm and 5.0 mm thick.

In some embodiments, the outer layer is between about 0.01 mm to 0.10 mmthick. In some embodiments, the outer layer is between about 0.10 mm to0.15 mm thick. In some embodiments, the outer layer is between about0.15 to 0.20 mm thick. In some embodiments, the outer layer is betweenabout 0.20 mm to 0.50 mm thick. In some embodiments, the outer layer isbetween about 0.50 mm and 1.0 mm thick.

In some embodiments, the inner layer (e.g., polymethyl methacrylate orother material) is about 1.0 mm thick and the outer layer (e.g., lead orother material) is about 0.16 mm thick. In some embodiments, the innerlayer (e.g., polymethyl methacrylate or other material) is between about0.1 mm to 1.0 mm thick and the outer layer (e.g., lead or othermaterial) is between about 0.01 mm to 0.10 mm thick. In someembodiments, the inner layer (e.g., polymethyl methacrylate or othermaterial) is between about 0.1 mm to 1.0 mm thick and the outer layer(e.g., lead or other material) is between about 0.10 mm to 0.20 mmthick. In some embodiments, the inner layer (e.g., polymethylmethacrylate or other material) is between about 1.0 mm to 2.0 mm thickand the outer layer (e.g., lead or other material) is between about 0.15mm to 0.50 mm thick. In some embodiments, the inner layer (e.g.,polymethyl methacrylate or other material) is between about 2.0 mm to5.0 mm thick and the outer layer (e.g., lead or other material) isbetween about 0.25 mm to 1.0 mm thick.

As shown in FIG. 1, FIG. 4, and FIG. 5, in some embodiments, the cannula100 is terminated with a handle 140. In some embodiments, the proximalportion 120 further comprises a connector 150. In some embodiments, ahandle 140 and/or a radiation shielding pig 900 may be fitted to thecannula 100 via the connector 150. In some embodiments, the radiationshielding pig 900 further comprises a plunger mechanism. In someembodiments, the cannula 100 is assembled prior to inserting it into apatient. In some embodiments, the cannula 100 is not assembled prior toinsertion, for example the cannula 100 is assembled after the distalportion 110 is inserted it into a patient.

In some embodiments, the handle 140 and/or the pig 900 is attached tothe cannula 100 after the cannula 100 is inserted via the subtenonapproach. Without wishing to limit the present invention to any theoryor mechanism, it is believed that attaching the handle 140 and/or thepig 900 to the cannula 100 after the cannula 100 has been inserted isadvantageous because the handle 140 and/or the pig 900 would notinterfere with the placement of the cannula 100. Additionally, theplacement of the cannula 100 may be easier because the handle 140 and/orpig 900, which may be bulky, would not interfere with the physicalfeatures of the patient.

Tip of Cannula, Indentation Tip

The distal portion 110 comprises a tip 200. In some embodiments, thedistal portion 110 comprises a tip 200 having a rounded shape (see FIG.2). In some embodiments, the tip 200 is blunt-ended. In someembodiments, the tip 200 of the distal portion 110 is open. In someembodiments, the tip 200 of the distal portion 110 is closed. In someembodiments, the distal portion 110 has a tip 200 wherein the tip 200 isblunt so as to prevent damage to blood vessels and/or nerves in theperiocular tissues and to pass smoothly over the sclera 235. In someembodiments, the tip 200 of the distal portion 110 further comprises aprotuberance (e.g., indentation tip 600) projecting from the cannula 100so as to indent the sclera 235 and functions as a visual aid to guidethe distal portion 110 of the cannula 100 to the correct position at theback of the eye (for example, see FIG. 2). In some embodiments, theindentation of the sclera 235 may be observed in the posterior pole ofthe eye by viewing through the pupil.

In some embodiments, the protuberance (e.g., indentation tip 600) isover the RBS (see FIG. 2). In some embodiments, the combined thicknessof the cannula wall and the indentation tip 600 (which may both comprisestainless steel) is about 0.33 mm thick and the RBS thus creates x-raysthat deposit more than 1% of the energy radiated by the RBS beyond 1 cm.

In some embodiments, the protuberance (e.g., indentation tip 600) isbetween about 0.01 mm and 0.10 mm thick. In some embodiments, theprotuberance (e.g., indentation tip 600) is between about 0.10 mm and0.20 mm thick. In some embodiments, the indentation tip 600 is betweenabout 0.20 mm and 0.33 mm thick. In some embodiments, the indentationtip 600 is between about 0.33 and 0.50 mm thick. In some embodiments,the indentation tip 600 is between about 0.50 mm and 0.75 mm thick. Insome embodiments, the indentation tip 600 is between about 0.75 mm and1.0 mm thick. In some embodiments, the indentation tip 600 is betweenabout 1.0 mm and 5.0 mm thick.

Light Source on the Cannula

In some embodiments, the distal portion 110 comprises a tip 200 and alight source 610 disposed at the tip 200 (see FIG. 2). In someembodiments, the distal portion 110 comprises a light source 610 thatruns a portion of the length of the distal portion 110. In someembodiments, the cannula 100 comprises a light source 610 that runs thelength of the cannula 100. Without wishing to limit the presentinvention to any theory or mechanism, it is believed that a light source610 that runs the length of the cannula 100 may be advantageous becauseilluminating the entire cannula 100 may assist the user (e.g.,physician, surgeon) in guiding the placement of the cannula 100 and/orobserving the physical structures in the area of placement.

In some embodiments, the light source 610 comprises a light-emittingdiode (LED) at the tip 200 of the cannula 100. The LED light may be seenthrough transillumination and may help guide the surgeon to the correctpositioning of the cannula 100. In some embodiments, the light source610 is directed through the cannula 100 by fiberoptics. In someembodiments, a light source 610, an indentation tip 600, and a window510 or an orifice 500 are coaxial.

In some embodiments, the light source 610 illuminates the target area.In some embodiments, the light source 610 illuminates a portion of thetarget area. In some embodiments, the light source 610 illuminates thetarget area and a non-target area. As used herein, a “target area” isthe area receiving about 100% of the intended therapeutic radiationdose. In some embodiments, the cannula 100 comprises a light source 610that illuminates more than the targeted radiation zone. Without wishingto limit the present invention to any theory or mechanism, it isbelieved that a light 610 is advantageous because a light 610 may createa diffuse illumination through lateral scattering that may be used inlieu of an indirect ophthalmoscope light. The light from the lightsource 610 may extend beyond the lesion to make reference points (e.g.,optic nerve, fovea, vessels) visible which may help orient the user(e.g., physician, surgeon).

In some embodiments, a part of or the entire cannula 100 glows. This mayallow the user (e.g., physician, surgeon) to observe the insertion ofthe cannula 100 and/or observe the target. In some embodiments, thecannula 100 is not illuminated in the area that is to be placed over thetarget (e.g., everything but the target is illuminated).

Radionuclide Brachytherapy Source

According to the Federal Code of Regulations, a radionuclidebrachytherapy source (RBS) comprises a radionuclide encased in anencapsulation layer. For example, the Federal Code of Regulationsdefines a radionuclide brachytherapy source as follows:

“A radionuclide brachytherapy source is a device that consists of aradionuclide which may be enclosed in a sealed container made of gold,titanium, stainless steel, or platinum and intended for medical purposesto be placed onto a body surface or into a body cavity or tissue as asource of nuclear radiation for therapy.”

The present invention features a novel radionuclide brachytherapy source(“RBS”). The RBS of the present invention is constructed in a mannerthat is consistent with the Federal Code of Regulations, but is notlimited to the terms mentioned in the Code. For example, the RBS of thepresent invention may optionally further comprise a substrate (discussedbelow). Also, for example, in addition to being enclosed by thementioned “gold, titanium, stainless steel, or platinum”, in someembodiments the radionuclide (isotope) of the present invention may beenclosed by a combination of one or more of “gold, titanium, stainlesssteel, or platinum”. In some embodiments, the radionuclide (isotope) ofthe present invention may be enclosed by one or more layers of an inertmaterial comprising silver, gold, titanium, stainless steel, platinum,tin, zinc, nickel, copper, other metals, ceramics, or a combination ofthese.

The RBS may be constructed in a number of ways, having a variety ofdesigns and/or shapes and/or distributions of radiation. In someembodiments, the RBS comprises a substrate 361, a radioactive isotope362 (e.g., Strontium-90), and an encapsulation. FIG. 14E. In someembodiments, the isotope 362 is coated on the substrate 361, and boththe substrate 361 and isotope 362 are further coated with theencapsulation. In some embodiments, the radioactive isotope 362 isembedded in the substrate 361. In some embodiments, the radioactiveisotope 362 is part of the substrate 361 matrix. In some embodiments,the encapsulation may be coated onto the isotope 362, and optionally, aportion of the substrate 361. In some embodiments, the encapsulation iscoated around the entire substrate 361 and the isotope 362. In someembodiments, the encapsulation encloses the isotope 362. In someembodiments, the encapsulation encloses the entire substrate 361 and theisotope 362. In some embodiments, the radioactive isotope 362 is anindependent piece and is sandwiched between the encapsulation and thesubstrate 361.

The RBS is designed to provide a controlled projection of radiation in arotationally symmetrical (e.g., circularly symmetrical) shape onto thetarget. In some embodiments, the RBS has an exposure surface that has arotationally symmetrical shape to provide for the projection of arotationally symmetrical irradiation onto the target.

A shape having n sides is considered to have n-fold rotational symmetryif n rotations each of a magnitude of 360°/n produce an identicalfigure. In some embodiments, shapes described herein as beingrotationally symmetrical are shapes having n-fold rotational symmetry,wherein n is a positive integer of 3 or greater.

In some embodiments, the rotationally symmetrical shape has at least5-fold rotational symmetry (n=5). In some embodiments, the rotationallysymmetrical shape has at least 6-fold rotational symmetry (n=6). In someembodiments, the rotationally symmetrical shape has at least 7-foldrotational symmetry (n=7). In some embodiments, the rotationallysymmetrical shape has at least 8-fold rotational symmetry (n=8). In someembodiments, the rotationally symmetrical shape has at least 9-foldrotational symmetry (n=9). In some embodiments, the rotationallysymmetrical shape has at least 10-fold rotational symmetry (n=10). Insome embodiments, the rotationally symmetrical shape has infinite-foldrotational symmetry (n=∞). Examples of rotationally symmetrical shapessuch as a circle, a square, an equilateral triangle, a hexagon, anoctagon, a six-pointed star, and a twelve-pointed star can be found inFIG. 14F.

Without wishing to limit the present invention to any theory ormechanism, it is believed that the rotationally symmetrical geometryprovides a fast fall off at the target periphery. In some embodiments,the rotationally symmetrical geometry provides a uniform fall off ofradiation at the target periphery. In some embodiments, the fast falloff of radiation at the target periphery reduces the volume and/or areairradiated.

Rotationally Symmetrical Exposure Surface Controlled by the Shape of theSubstrate

In some embodiments, a surface on the substrate 361 is shaped in amanner to provide a controlled projection of radiation in a rotationallysymmetrical shape onto the target. For example, in some embodiments, thebottom surface 363 of the substrate 361 is rotationally symmetrical,e.g., circular, hexagonal, octagonal, decagonal, and/or the like. Whenthe radioactive isotope 362 is coated onto such rotationally symmetricalbottom surface 363 of the substrate 362 a rotationally symmetricalexposure surface is created.

In some embodiments, the substrate 361 is a disk 405, for example a disk405 having a height 406 and a diameter 407 (see FIG. 14). In someembodiments, the height 406 of the disk 405 is between about 0.1 mm and10 mm. For example, in some embodiments, the height 406 of the disk 405is between about 0.1 to 0.2 mm. In some embodiments, the height 406 ofthe disk 405 is between about 0.2 to 2 mm, such as 1.5 mm. In someembodiments, the height 406 of the disk 405 is between about 2 to 5 mm.In some embodiments, the height 406 of the disk 405 is between about 5to 10 mm. In some embodiments, the diameter 407 of the disk 405 isbetween about 0.1 to 0.5 mm. In some embodiments, the diameter 407 ofthe disk is between about 0.5 to 10 mm. For example, in someembodiments, the diameter 407 of the disk 405 is between about 0.5 to2.5 mm, such as 2 mm. In some embodiments, the diameter 407 of the disk405 is between about 2.5 to 5 mm. In some embodiments, the diameter 407of the disk 405 is between about 5 to 10 mm. In some embodiments, thediameter 407 of the disk 405 is between about 10 to 20 mm.

The substrate 361 may be constructed from a variety of materials. Forexample, in some embodiments the substrate 361 is constructed from amaterial comprising, a silver, an aluminum, a stainless steel, tungsten,nickel, tin, zirconium, zinc, copper, a metallic material, a ceramicmaterial, a ceramic matrix, the like, or a combination thereof. In someembodiments, the substrate 361 functions to shield a portion of theradiation emitted from the isotope 362. For example, in someembodiments, the substrate 361 has thickness such that the radiationfrom the isotope 362 cannot pass through the substrate 361. In someembodiments, the density times the thickness of the substrate 361 isbetween about 0.01 g/cm² to 10 g/cm².

The substrate 361 may be constructed in a variety of shapes. Forexample, the shape may include but is not limited to a cube, a sphere, acylinder, a rectangular prism, a triangular prism, a pyramid, a cone, atruncated cone, a hemisphere, an ellipsoid, an irregular shape, thelike, or a combination of shapes. As shown in FIG. 14, in someembodiments, the substrate 361 may have a generally rectangular sidecross section. In some embodiments, the substrate 361 may have agenerally triangular or trapezoidal side cross section. In someembodiments, the substrate 361 may have generally circular/oval sidecross section. The side cross section of the substrate 361 may be acombination of various geometrical and/or irregular shapes.

Rotationally Symmetrical Exposure Surface Controlled by the Shape of theIsotope

In some embodiments, the isotope 362 is coated on the entire substrate361. In some embodiments, the isotope 362 is coated or embedded on aportion of the substrate 361 (e.g., on the bottom surface 363 of thesubstrate 361) in various shapes. For example, the coating of theisotope 362 on the substrate 361 may be in the shape of a rotationallysymmetrical shape, e.g., a circle, a hexagon, an octagon, a decagon, orthe like. The rotationally symmetrical shape of the isotope 362 coatingon the bottom surface 363 of the substrate 361 provides for therotationally symmetrical exposure surface, which results in a controlledprojection of radiation in a rotationally symmetrical shape onto thetarget.

Rotationally Symmetrical Exposure Surface Controlled by the Shape of theEncapsulation

In some embodiments, the encapsulation is constructed to provide arotationally symmetrical exposure surface for a controlled projection ofradiation having a rotationally symmetrical shape on the target. In someembodiments, the encapsulation has variable thickness so that it shieldssubstantially all of the radiation in some portions and transmitssubstantially all of the radiation in other portions. For example, inone embodiment, the density times the thickness of the encapsulation is1 g/cm² at distances greater than 1 mm from the center of theradioactive portion of the source and the density times the thickness ofthe encapsulation is 0.01 g/cm² at distances less than 1 mm from thecenter of the radioactive portion of the source. For a Sr-90 source,this encapsulation would block substantially all of the radiationemitted more than 1 mm from the center of the radioactive portion of thesource, yet permit substantially all of the radiation emitted within 1mm of the center of the radioactive portion of the source to passthrough. In some embodiments, the thickness of the encapsulation variesbetween 0.001 g/cm² and 10 g/cm². In some embodiments, rotationallysymmetric shapes of the high and low density regions as described aboveare used.

The encapsulation may be constructed from a variety of materials, forexample from one or more layers of an inert material comprising a steel,a silver, a gold, a titanium, a platinum, another bio-compatiblematerial, the like, or a combination thereof. In some embodiments, theencapsulation is about 0.01 mm thick. In some embodiments, theencapsulation is between about 0.01 to 0.10 mm thick. In someembodiments, the encapsulation is between about 0.10 to 0.50 mm thick.In some embodiments, the encapsulation is between about 0.50 to 1.0 mmthick. In some embodiments, the encapsulation is between about 1.0 to2.0 mm thick. In some embodiments, the encapsulation is more than about2.0 mm thick, for example about 3, mm, about 4 mm, or about 5 mm thick.In some embodiments, the encapsulation is more than about 5 mm thick,for example, 6 mm, 7 mm, 8 mm, 9 mm, or 10 mm thick.

Rotationally Symmetrical Exposure Surface Controlled by Other Components

In some embodiments, a radiation-shaper 366 can provide a controlledprojection of radiation in a rotationally symmetrical shape onto thetarget. (FIG. 14G). A radiation-shaper 366 comprises a radio-opaqueportion and a substantially radioactive transparent portion (hereinafter“window 364”). In some embodiments, the radiation shaper 366 is placedunder the RBS. The radiation from the portion of the RBS that overlapsthe window 364 is emitted through the window 364 toward the target, andthe radiation from the portion that does not overlap the window 364 isblocked by the radio-opaque portion from reaching the target. Thus, awindow 364 having a rotationally symmetrical shape will allow for aprojection of a rotationally symmetrical irradiation of the target.

In some embodiments, the window 510 (or orifice 500) of the cannula 100may be the window 364 of the radiation shaper 366 to provide acontrolled projection of radiation in a rotationally symmetrical shapeonto the target. For example, in some embodiments, the window 510 iscircular.

As discussed, a controlled projection of radiation in a rotationallysymmetrical shape onto the target allows for a fast fall off at the edgeof the target. Also intended to be within the scope of the presentinvention are the various combinations of arrangements of the componentsof the RBS and/or cannula 100 to produce a controlled projection ofradiation in a rotationally symmetrical shape onto a target. Based onthe disclosures herein, one of ordinary skill would know how to developthese various combinations to produce a controlled projection ofradiation in a rotationally symmetrical shape onto the target allows fora fast fall off at the edge of the target. Fast fall off at the edge ofthe target may also be enhanced by recessing the RBS in a well havingdeep radio opaque walls. For example, FIG. 21 shows an RBS recessed in awell with deep walls, where the walls can enhance and even faster falloff of radiation at the target edge.

Isotopes & Radioactivity

Various isotopes may be employed within the scope of the presentinvention. Beta emitters such as phosphorus 32 and strontium 90 werepreviously identified as being useful radioactive isotopes because theyare beta emitters that have limited penetration and are easily shielded.In some embodiments, the isotope 362 comprises phosphorus 32 (P-32),strontium-90 (Sr-90), ruthenium 106 (Ru-106), yttrium 90 (Y-90), thelike, or a combination thereof.

Although they are distinctly different from beta emitters, in someembodiments, the RBS may comprise an isotope 362 such as a gamma emitterand/or an alpha emitter. For example, in some embodiments, the isotope362 comprises iodine 125 (I-125), palladium 103 (Pd-103), cesium 131(Cs-131), cesium 137 (Cs-137), cobalt 60 (co-60), the like, or acombination thereof. In some embodiments, the RBS comprises acombination of various types of isotopes 362. For example, in someembodiments, the isotope 362 comprises a combination of Sr-90 and P-32.In some embodiments, the isotope 362 comprises a combination of Sr-90and Y-90.

To achieve a particular dose rate at the target, the activity of theisotope that is to be used is determined for a given distance betweenthe isotope and the target. For example, if the radiation source is astrontium-yittrium-90 titanate internally contained in a silver-cladmatrix forming a disk about 4 mm in diameter and having a height ofabout 0.06 mm, sealed in titantium that is about 0.8 mm thick on oneflat surface of the disk and around the circumference and is about 0.1mm thick on the opposite flat surface of the disk (target side of thedisk), the target is at a depth of about 1.5 mm (in tissue) and thedesired dose rate is about 24 Gy/min at the target, an activity of about100 mCi may be used. Or, if all aspects of the source are kept the sameexcept that the diameter of the strontium-yittrium-90 titanateinternally contained in a silver-clad matrix disk is about 3 mm indiameter, the target is at a depth of about 2.0 mm (in tissue) and thedesired dose rate is about 18 Gy/min at the target, an activity of about150 mCi may be used. Or, if all aspects of the source are kept the sameexcept that the diameter of the strontium-yittrium-90 titanateinternally contained in a silver-clad matrix disk is about 3 mm indiameter, the target is at a depth of about 0.5 mm (in tissue) and thedesired dose rate is about 15 Gy/min at the target, an activity of about33 mCi may be used. Or, if all aspects of the source are kept the sameexcept that the diameter of the strontium-yittrium-90 titanateinternally contained in a silver-clad matrix disk is about 2 mm indiameter, the target is at a depth of about 5.0 mm (in tissue) and thedesired dose rate is about Gy/min at the target, an activity of about7100 mCi may be used.

In some embodiments, the isotope has about 5 to 20 mCi, for example, 10mCi.

In some embodiments, to achieve a particular dose rate at the target,the radioactivity of the isotope 362 that is to be used is determinedfor a given distance between the isotope 362 and the target. Forexample, if the Sr-90 isotope 362 is about 5 mm from the target (intissue) and the desired dose rate is about 20 Gy/min at the target, aSr-90 isotope 362 having a radioactivity of about 5,000 mCi may be used.Or, if the P-32 isotope 362 is about 2 mm from the target and thedesired dose rate is about 25 Gy/min at the target, a P-32 isotope 362having a radioactivity of about 333 mCi may be used.

In some embodiments, the isotope 362 has an activity of between about0.5 to 5 mCi. In some embodiments, the isotope 362 has an activity ofbetween about 5 to 10 mCi. In some embodiments, the isotope 362 has anactivity of between about to 50 mCi. In some embodiments, the isotope362 has an activity of between about 50 to 100 mCi. In some embodiments,the isotope 362 has an activity of between about 100 to 500 mCi. In someembodiments, the isotope 362 has an activity of between about 500 to1,000 mCi. In some embodiments, the isotope has an activity of betweenabout 1,000 to 5,000 mCi. In some embodiments, the isotope has anactivity of between about 5,000 to 10,000 mCi. In some embodiments, theisotope 362 has an activity of more than about 10,000 mCi.

Guide & Memory Wire

In some embodiments, the RBS (e.g., substrate and/or encapsulation) isattached to the guide wire 350 or ribbon that runs through the cannula.In some embodiments, the attachment of the substrate 361 and/or theencapsulation to the guide wire 350 may be achieved using a variety ofmethods. In some embodiments, the substrate 361 and/or encapsulation isattached by welding. In some embodiments, the substrate 361 and/orencapsulation is attached to the guide wire 350 by glue. In someembodiments, the substrate 361 and/or encapsulation is attached to theguide wire 350 (or ribbon) by being enveloped in a plastic sleeve havingan extension which forms a plastic guide wire 350. In some embodiments,this may be achieved using a method such as heat shrink tubing. In someembodiments, the substrate 361 and/or encapsulation is coated onto theguide wire 350 or the ribbon that runs through the cannula.

In some embodiments, the RBS is in the form of a deployable wafer. Insome embodiments, the wafer is in the shape of a cylinder, an ellipse,or the like. In some embodiments, the wafer comprises nickel titanium(NiTi) either doped with or surface coated with a radioisotope thatopens up when deployed. In some embodiments, the wafer is coated with abio-inert material if it is to be left in place for an extended periodof time.

In some embodiments, the memory wire 300 comprises the RBS. In someembodiments, the memory wire 300 functions like a disk 405 orseed-shaped RBS 400. The seed-shaped RBS 400 may have a spherical orellipsoidal shape. The shape of the seed-shaped RBS 400 is not limitedto the aforementioned shapes. In some embodiments, the shape of theseed-shaped RBS 400 is determined by dimensions so as to maximize thearea and/or the volume that can pass through a cannula 100 per thecannula 100 description. For example, in some embodiments, the RBS is inthe shape of a curved cylinder. In some embodiments, the curved cylinderhas a rounded distal end and a rounded proximal end so to furtheraccommodate the curvature of the cannula 100.

In some embodiments, the RBS is for inserting into a cannula 100. Insome embodiments, the RBS is designed to traverse a length of thecannula 100. In some embodiments, more than one RBS is used to deliverradiation to a target. For example, in some embodiments, two disks 405may be used inside the cannula 100.

Construction of RBS Wherein More than 1% of the Total Source RadiationEnergy Flux Extends Beyond a Distance of 1 cm

Without wishing to limit the present invention to any theory ormechanism, it is believed that an effective design for a medical devicefor treating wet age-related macular degeneration should have aradiation dose distribution such that greater than 1% of the totalsource radiation energy flux (e.g., total radiation energy flux at thesource center along the line l_(R)) is transmitted to greater than orequal to 1 cm distance from the RBS (along the line l_(R)).

In some embodiments, the present invention has a RBS that deposits lessthan about 99% (e.g., 98%, 97%, etc.) of its total source radiationenergy flux at distance of 1 cm or less from the RBS.

In some embodiments, the present invention has a RBS that deposits morethan 1% (e.g., 2%, 3%, 4% etc.) of its total source radiation energyflux at distance of 1 cm or more from the RBS. In some embodiments, thepresent invention has a RBS that deposits between 1% to 15% of its totalsource radiation energy flux at distance of 1 cm or more from the RBS.

In some embodiments, the interaction of the isotope radiation (e.g.,beta radiation) with the encapsulation (e.g., gold, titanium, stainlesssteel, platinum) converts some of the beta radiation energy to anemission of bremsstrahlung x-rays. These x-rays may contribute to theentire radiotherapy dose both in the prescribed target area and alsopenetrate further than beta radiation. Thus such a device as constructedwith the aforementioned desirable attributes with a primary beta sourcewill produce a radiation pattern in which 1% or greater of all radiationfrom the source is absorbed at a distance greater than 1 cm (e.g., theradiation energy flux at a distance of 1 cm away from the center of thetarget is greater than 1% of the total source radiation energy flux).See Table 3. In some embodiments, the present invention features adevice wherein the RBS comprises an isotope, wherein the isotopecomprises a beta radiation isotope, wherein about 1% of the total sourceradiation energy flux falls at a distance greater than 1 cm from thecenter of the target.

Without wishing to limit the present invention to any theory ormechanism, it is believed that it is desirable to construct the RBS asdescribed in the present invention for ease of manufacturing and so itis inert to the body (due to encasing the RBS in a bio-compatiblematerial). A RBS that is constructed in this manner may produce aradiation pattern comprising beta rays, x-rays, or both beta rays andx-rays, such that greater than 1% of the total source radiation energyflux will extend a distance greater that about 1 cm.

In FIG. 28, Table 3 is a listing for non-limiting examples of suchSr-90-constructed radioactive seeds.

In some embodiments, the RBS is in the form of a deployable wafer. Insome embodiments, the wafer is in the shape of a cylinder, an ellipse,or the like. In some embodiments, the wafer comprises a nickel titanium(NiTi) substrate, either doped with or surface coated with an isotope362 and then encapsulated, that opens up when deployed. In someembodiments, the wafer is encapsulated with a bio-inert material if itis to be left in place for an extended period of time.

In some embodiments, the RBS is for inserting into a cannula 100. Insome embodiments, the RBS is designed to traverse a length of thecannula 100. In some embodiments, more than one RBS is used to deliverradiation to a target. For example, in some embodiments, two radioactivedisks 405 or seed-shaped RBSs 400 are inserted into the cannula 100.

The Memory Wire

In some embodiments, the cannula 100 of the present invention comprisesa guide wire 350 inserted within the cannula 100, whereby the guide wire350 functions to push a RBS toward the tip 200 of the distal portion110.

In some embodiments, the cannula 100 comprises a memory wire 300 (FIG.2). In some embodiments, the cannula 100 comprises a guide wire 350 anda memory wire 300, wherein the guide wire 350 is connected to the memorywire 300. In some embodiments, the cannula 100 comprises a guide wire350 and a memory wire 300, wherein the guide wire 350 and the memorywire 300 are the same wire. In some embodiments, the memory wire 300 maybe extended from or retracted into the cannula 100 as the guide wire 350is advanced or retracted, respectively.

In some embodiments, the memory wire 300 assumes a shape once it isdeployed to the tip 200 of the cannula 100. In some embodiments, thememory wire 300 comprises a material that can take a desirable shape foruse in delivering the radiation to a posterior portion of the eye. Itwill be understood by persons having skill in the art that many shapesof memory wires may be utilized to provide a shape consistent with thatrequired or desired for treatment. In some embodiments, the memory wire300 is in the shape of a spiral, a flat spiral 310, a ribbon, the like,or a combination thereof (FIG. 2). In some embodiments, the desirableshape of the memory wire 300 for delivering radiation may not allow forthe memory wire 300 to be inserted into the cannula 100. Therefore, insome embodiments, the memory wire 300 is capable of being straightenedso that it may be inserted into the cannula 100. In some embodiments,the memory wire 300 may form a shape (e.g., a spiral) when extended fromthe cannula 100. In some embodiments, the memory wire 300 having a shape(e.g., a flat spiral 310) may be straightened upon being retracted intothe cannula 100. In some embodiments, the memory wire 300 extends fromthe tip 200 of the distal portion 110 of the cannula 100.

In some embodiments, the memory wire 300 comprises an alloy ofnickel-titanium (NiTi). However, it will be understood by persons havingskill in the art that any metal, or alloy, or other material such asspring steel, shape memory nickel-titanium, super-elasticnickel-titanium, plastics and other metals and the like, can be used tocreate the memory wire 300.

In some embodiments, the memory wire 300 comprises the RBS (e.g.,substrate 261, isotope 362 and/or encapsulation). In some embodiments,the memory wire 300 has the isotope 362 deposited on it and is furtherencapsulated, thus the memory wire 300 comprises the RBS. In someembodiments, the distal end 320 of the memory wire 300 comprises the RBS(e.g., isotope 362 and encapsulation), for example the distal end 320 iscoated with an isotope and further encapsulated. In some embodiments,the distal end 320 of the memory wire 300 comprises the RBS and theremaining portion of the memory wire 300 and/or the guide wire 350 mayact to shield neighboring areas from the radiation. In some embodiments,the RBS and/or isotope 362 are applied to the memory wire 300 as a thincoating. In some embodiments, the RBS is applied to the memory wire 300as solid pieces.

In some embodiments, the memory wire 300 functions like a disk 405 orseed-shaped RBS 400. The seed-shaped RBS 400 may have a spherical shape,cylindrical shape, or an ellipsoidal shape. The shape of the seed 400 isnot limited to the aforementioned shapes. In some embodiments, the shapeof the seed 400 is determined by dimensions so as to maximize the areaand/or the volume that can pass through a cannula 100 per the cannula100 description. For example, in some embodiments, the RBS is in theshape of a curved cylinder. In some embodiments, the curved cylinder hasa rounded distal end and a rounded proximal end so to furtheraccommodate the curvature of the cannula 100

In some embodiments, the memory wire 300 is advanced toward the tip 200of the cannula 100, allowing the memory shape to form. Without wishingto limit the present invention to any theory or mechanism, it isbelieved that the memory shape is advantageous because when it isformed, it concentrates the RBS in the desired shape. Further, variousshapes may be used to achieve a certain concentration of radiationand/or to achieve a certain area of exposure. The shape may becustomized to achieve particular desired results. For example, a lowradiation intensity may be delivered when the wire exposed at the distalend is substantially straight, and a higher radiation intensity may bedelivered with the wire exposed at the distal end is coiled up wherethere is more bundling of the radiation at the area.

In some embodiments, the memory wire 300 is a flat wire similar to aribbon. In some embodiments, the ribbon may be coated (e.g., with anisotope and encapsulation) on only one edge, and when the ribbon iscoiled, the edge that is coated with radiation material will concentratethe RBS, and the other edge not comprising radiation material may act asa shield.

In some embodiments, the RBS (e.g., substrate 361 and/or encapsulationand isotope 362) is attached to the guide wire 350. In some embodiments,the attachment of the substrate 361 and/or the encapsulation to theguide wire 350 may be achieved using a variety of methods. In someembodiments, the substrate 361 and/or encapsulation is attached bywelding. In some embodiments, the substrate 361 and/or encapsulation isattached to the guide wire 350 by glue. In some embodiments, thesubstrate 361 and/or encapsulation is attached to the guide wire 350 bybeing enveloped in a plastic sleeve having an extension, which forms aplastic guide wire 350. In some embodiments, this may be achieved usinga method such as heat shrink tubing.

Distal Chamber and Balloon

In some embodiments, the cannula 100 comprises a distal chamber 210disposed at the end of the distal portion 110 (see FIG. 2). The distalchamber 210 allows a memory wire 300 to coil in a protected environment.In some embodiments, the distal chamber 210 is in the shape of a disc.In some embodiments, the distal chamber 210 is in the shape of atwo-dimensional tear drop.

In some embodiments, the distal chamber 210 is rounded at the tip andhas a width that is about the same as the width of the cannula 100. Insome embodiments, the distal chamber 210 is hollow. The distal chamber210 allows a memory wire 300 or a RBS (e.g., disk 405, seed-shaped RBS400) to be inserted into it. In some embodiments, the memory wire 300curls into a coil in the distal chamber 210. In some embodiments,coiling of the memory wire 300 inside the distal chamber 210concentrates the RBS. Without wishing to limit the present invention toany theory or mechanism, it is believed that concentrating the RBSallows for a faster procedure. Additionally, this may allow for use of alower activity RBS. In some embodiments, the distal chamber 210 keepsthe memory wire 300 enclosed in a controlled space, allowing the memorywire 300 to coil into the distal chamber 210 and be retracted into thecannula 100 without concern of the memory wire 300 breaking off orbecoming trapped in surrounding structures. In some embodiments, thedistal chamber 210 is oriented to lay flat against the back of the eye(e.g., against the sclera).

In some embodiments, the distal chamber 210 further comprises aprotuberance (e.g., distal chamber indentation tip) projecting from thedistal chamber 210 so as to indent the sclera and functions to guide thedistal chamber 210 to the correct position at the back of the eye. Insome embodiments, the distal chamber indentation tip is disposed on thefront of the distal chamber 210, the front being the part that hascontact with the patient's eye. In some embodiments, the distal chamberindentation trip allows a physician to identify the location of the tip200 of the cannula 100 over the target area. In some embodiments, thedistal chamber 210 further comprises a light source 610.

In some embodiments, the distal chamber 210 comprises a metal, aplastic, the like, or a combination thereof. In some embodiments, thedistal chamber 210 comprises one or more layers of metals and/or alloys(e.g., a gold, a stainless steel). In some embodiments, the distalchamber 210 comprises a material that does not shield the RBS. In someembodiments, the distal chamber 210 comprises an orifice 500 and/or awindow 510 disposed on the front of the distal chamber 210. In someembodiments, the distal chamber 210 further comprises a radiation shielddisposed on the back of the distal chamber 210 and/or a side of thedistal chamber 210. Without wishing to limit the present invention toany theory or mechanism, it is believed that a distal chamber 210comprising a radiation shield disposed on the back and/or a side of thedistal chamber 210 is advantageous because it would prevent theradiation from being directed to an area other than the target area(e.g., the patient's optic nerve).

In some embodiments, the cannula 100 comprises an expandable tip (e.g.,a balloon). In some embodiments, the expandable tip may be expandedusing a gas or a liquid, for example balanced salt solution (BSS). Insome embodiments, the expandable tip is first expanded, and then the RBS(e.g., disk 405, seed-shaped RBS 400) or the radioactive portion of thememory wire 300 is deployed. Without wishing to limit the presentinvention to any theory or mechanism, it is believed that an expandabletip is advantageous because it could act as a guide to position thecannula 100 in the correct location. The physician may be able toconfirm the position of the cannula 100 because the expanded tip wouldcreate a convexity in the sclera 235. The expandable tip may furthercomprise a shield for preventing radiation from projecting to an areaother than the target area (e.g., the patient's eye).

In some embodiments, the expandable tip is a balloon. In someembodiments, the balloon in its non-expanded state covers the distalportion 110 of the cannula 100 like a sheath.

Doses

As used herein, the term “lateral” and/or “laterally” refers to in thedirection of any line that is perpendicular to line l_(R), wherein linel_(R) is the line derived from connecting the points l_(S) and l_(T),wherein l_(s) is the point located at the center of the RBS and l_(t) isthe point located at the center of the target (see FIG. 10, FIG. 12).

As used herein, the term “forwardly” refers to in the direction ofand/or along line l_(R) from l_(S) through l_(T), (see FIG. 10)

As used herein, the term “substantially uniform” refers to a group ofvalues (e.g., two or more values) wherein each value in the group is noless than about 90% of the highest value in the group. For example, anembodiment wherein the radiation doses at a distance of up to about 1 mmfrom the center of the target are substantially uniform implies that anyradiation dose within the distance of up to about 1 mm away from thecenter of the target is no less than about 90% of the highest radiationdose within that area (e.g., the total target center radiation dose).For example, if a group of relative radiation doses within a distance ofup to about 1 mm away from the center of the target are measured to be99, 97, 94, 100, 92, 92, and 91, the relative radiation doses aresubstantially uniform because each value in the group is no less than90% of the highest value in the group (100).

As used herein, the term “isodose” (or prescription isodose, ortherapeutic isodose) refers to the area directly surrounding the centerof the target wherein the radiation dose is substantially uniform (seeFIG. 13).

Without wishing to limit the present invention to any theory ormechanism, the devices and methods of the present invention are believedto be effective by delivering a substantially uniform dose to the entiretarget region (e.g., neovascular tissue), or a non-uniform dose, inwhich the center of the target has dose that is about 2.5× higher thanthe dose at the boundary regions of the target.

In some embodiments, a dose of about 16 Gy is delivered to the target.In some embodiments, a dose of about 16 Gy to 20 Gy is delivered to thetarget. In some embodiments, a dose of about 20 Gy is delivered to thetarget. In some embodiments, a dose of about 24 Gy is delivered to thetarget. In some embodiments, a dose of about 20 Gy to 24 Gy is deliveredto the target. In some embodiments, a dose of about 30 Gy is deliveredto the target. In some embodiments, about 24 Gy to 30 Gy is delivered tothe target. In some embodiments, a dose of about 30 Gy to 50 Gy isdelivered to the target. In some embodiments, a dose of about 50 Gy to100 Gy is delivered to the target. In some embodiments, a dose of about75 Gy is delivered to the target.

Dose Rates

The medical radiation community believes as medico-legal fact that lowdose rate irradiation (e.g., less than about 10 Gy/min) is preferredover high dose rate irradiation because high dose rate irradiation maycause more complications. For example, the scientific publication“Posttreatment Visual Acuity in Patients Treated with Episcleral PlaqueTherapy for Choroidal Melanomas: Dose and Dose Rate Effects” (Jones, R.,Gore, E., Mieler, W., Murray, K., Gillin, M., Albano, K., Erickson, B.,International Journal of Radiation Oncology Biology Physics, Volume 52,Number 4, pp. 989-995, 2002) reported the result “macula dose rates of111 cGy/h (+/−11.1 cGy/h) were associated with a 50% risk of significantvisual loss,” leading them to conclude “higher dose rates to the maculacorrelated strongly with poorer posttreatment visual outcome.”Furthermore, the American Brachytherapy Society (ABS) issued theirrecommendations in the scientific publication, “The AmericanBrachytherapy Society Recommendations for Brachytherapy of UvealMelanomas” (Nag, S., Quivey, J. M., Earle, J. D., Followill, D.,Fontanesi, J., and Finger, P. T., International Journal of RadiationOncology Biology Physics, Volume 56, Number 2, pp. 544-555, 2003)stating “the ABS recommends a minimum tumor I-125 dose of 85 Gy at adose rate of 0.60 to 1.05 Gy/h using AAPM TG-43 formalism for thecalculation of dose.” Thus, the medical standard of care requires lowdose rates.

Despite the teachings away from the use of high dose rates, theinventors of the present invention surprisingly discovered that a highdose rate (i.e., above about Gy/min) may be advantageously used to treatneovascular conditions.

In some embodiments, the dose rate delivered/measured at the target isgreater than 10 Gy/min (e.g., about 15 Gy/min, 20 Gy/min). In someembodiments, the dose rate delivered/measured at the target is betweenabout 10 Gy/min to 15 Gy/min. In some embodiments, the dose ratedelivered/measured at the target is between about 15 Gy/min to 20Gy/min. In some embodiments, the dose rate delivered/measured at thetarget is between about 20 Gy/min to 30 Gy/min. In some embodiments, thedose rate delivered/measured at the target is between about 30 Gy/minand 40 Gy/min. In some embodiments, the dose rate delivered/measured atthe target is between about 40 Gy/min to 50 Gy/min. In some embodiments,the dose rate delivered/measured at the target is between about 50Gy/min to 75 Gy/min. In some embodiments, the dose ratedelivered/measured at the target is between about 75 Gy/min to 100Gy/min. In some embodiments, the dose rate delivered/measured at thetarget is greater than about 100 Gy/min.

In some embodiments, about 16 Gy of radiation is delivered with a doserate of about 16 Gy/min for about 1 minute (as measured at the target).In some embodiments, about 20 Gy of radiation is delivered with a doserate of about 20 Gy/min for about 1 minute (as measured at the target).In some embodiments, about 25 Gy is delivered with a dose rate of about12 Gy/min for about 2 minutes (as measured at the target). In someembodiments, about 30 Gy of radiation is delivered with a dose rate ofgreater than about 10 Gy/min (e.g., 11 Gy/min) for about 3 minutes (asmeasured at the target). In some embodiments, about 30 Gy of radiationis delivered with a dose rate of about 15 Gy/min to 16 Gy/min for about2 minutes (as measured at the target). In some embodiments, about 30 Gyof radiation is delivered with a dose rate of about 30 Gy/min for about1 minute (as measured at the target). In some embodiments, about 40 Gyof radiation is delivered with a dose rate of about 20 Gy/min for about2 minutes (as measured at the target). In some embodiments, about 40 Gyof radiation is delivered with a dose rate of about 40 Gy/min for about1 minute (as measured at the target). In some embodiments, about 40 Gyof radiation is delivered with a dose rate of about 50 Gy/min for about48 seconds (as measured at the target). In some embodiments, about 50 Gyof radiation is delivered with a dose rate of about 25 Gy/min for about2 minutes (as measured at the target). In some embodiments, about 50 Gyof radiation is delivered with a dose rate of about 75 Gy/min for about40 seconds (as measured at the target). In some embodiments, a dose rateof about 75 Gy is delivered with a dose rate of about 75 Gy/min forabout 1 minute (as measured at the target). In some embodiments, a doserate of about 75 Gy is delivered with a dose rate of about 25 Gy/min forabout 3 minutes (as measured at the target).

In some embodiments, the target is exposed to the radiation betweenabout 0.01 seconds to about 0.10 seconds. In some embodiments, thetarget is exposed to the radiation between about 0.10 seconds to about1.0 second. In some embodiments, the target is exposed to the radiationbetween about 1.0 second to about 10 seconds. In some embodiments, thetarget is exposed to the radiation between about 10 seconds to about 15seconds. In some embodiments, the target is exposed to the radiationbetween about 15 seconds to 30 seconds. In some embodiments, the targetis exposed to the radiation between about 30 seconds to 1 minute. Insome embodiments, the target is exposed to the radiation between about 1minute to about 5 minutes. In some embodiments, the target is exposed tothe radiation between about 5 minutes to about 7 minutes. In someembodiments, the target is exposed to the radiation between about 7minutes to about 10 minutes. In some embodiments, the target is exposedto the radiation between about 10 minutes to about 20 minutes. In someembodiments, the target is exposed to the radiation between about 20minutes to about 30 minutes. In some embodiments, the target is exposedto the radiation between about 30 minutes to about 1 hour. In someembodiments, the target is exposed to the radiation for more than 1hour.

Doses, Dose Rates for Tumors

Without wishing to limit the present invention to any theory ormechanism, it is believed that for treating or managing conditions otherthan macula degeneration (e.g., tumors), a typical dose is expected tobe in the range of about 10 Gy to about 100 Gy, such as 85 Gy.Furthermore, it is believed that to irradiate from the exterior side ofthe eye where the radiation has to pass through the sclera, the RBSshould provide a dose rate of about 0.6 Gy/min to about 100 Gy/min tothe target. In some embodiments, for treating conditions other thanmacula degeneration (e.g., tumors), the RBS provides a dose rate ofgreater than about 10 Gy/min to about 20 Gy/min to the target. In someembodiments, the RBS provides a dose rate of greater than about 20 to 40Gy/min (e.g., 36 Gy/min) to the target. In some embodiments, the RBSprovides a dose rate of greater than about 40 to 60 Gy/min to thetarget. In some embodiments, the RBS provides a dose rate of greaterthan about 60 to 80 Gy/min to the target. In some embodiments, the RBSprovides a dose rate of greater than about 80 to 100 Gy/min to thetarget. In some embodiments, the dose rate that is chosen by a user(e.g. physicist, physician) to irradiate the tumor depends on one ormore characteristics (e.g., height/thickness of the tumor/lesion (e.g.,the thickness of the tumor may dictate what dose rate the user uses).

Without wishing to limit the present invention to any theory ormechanism, it is believed that the exposure time should be between about15 seconds to about 10 minutes for practical reasons. However, otherexposure times may be used. In some embodiments, the target is exposedto the radiation between about 0.01 seconds to about 0.10 seconds. Insome embodiments, the target is exposed to the radiation between about0.10 seconds to about 1.0 second. In some embodiments, the target isexposed to the radiation between about 1.0 second to about 10 seconds.In some embodiments, the target is exposed to the radiation betweenabout 10 seconds to about 15 seconds. In some embodiments, the target isexposed to the radiation between about 15 seconds to 30 seconds. In someembodiments, the target is exposed to the radiation between about 30seconds to 1 minute. In some embodiments, the target is exposed to theradiation between about 1 to 5 minutes. In some embodiments, the targetis exposed to the radiation between about 5 minutes to about 7 minutes.In some embodiments, the target is exposed to the radiation betweenabout 7 minutes to about 10 minutes. In some embodiments, the target isexposed to the radiation between about 10 minutes to about 20 minutes.In some embodiments, the target is exposed to the radiation betweenabout 20 minutes to about 30 minutes. In some embodiments, the target isexposed to the radiation between about 30 minutes to about 1 hour. Insome embodiments, the target is exposed to the radiation for more than 1hour.

Radiation Area, Radiation Profile

In some embodiments, the cannula 100 and/or RBSs of the presentinvention are designed to treat a small target area with a substantiallyuniform dose and are also designed so that the radiation dose declinesmore rapidly as measured laterally from the target as compared to theprior art (see FIG. 8). The prior art conversely teaches the advantagesof a substantially uniform dose over a larger diameter target and with aslower decline in radiation dose (as measured laterally) (e.g., U.S.Pat. No. 7,070,544 B2).

In some embodiments, the radiation dose rapidly declines as measuredlaterally from edge of an isodose (e.g., the area directly surroundingthe center of the target wherein the radiation dose is substantiallyuniform) (as shown in FIG. 8).

FIG. 11 shows a non-limiting example of a radiation dose profile (asmeasured laterally) of a 1 mm source comprised of Sr-90. In someembodiments, the radiation dose at a distance of about 0.5 mm from thecenter of the target is about 10% less than the dose on the central axisof the target. In some embodiments, the radiation dose at a distance ofabout 1.0 mm from the center of the target is about 30% less than thedose on the central axis of the target. In some embodiments, theradiation dose at a distance of about 2.0 mm from the center of thetarget is about 66% less than the dose on the central axis of thetarget. In some embodiments, the radiation dose at a distance of about3.0 mm from the center of the target is about 84% less than the dose onthe central axis of the target. In some embodiments, the radiation doseat a distance of about 4.0 mm from the center of the target is about 93%less than the dose on the central axis of the target.

In some embodiments, the dose on the central axis of the target is thedose delivered at the choroidal neovascular membrane (CNVM). In someembodiments the radiation dose extends away from the target (e.g.,choroidal neovascular membrane) in all directions (e.g., laterally,forwardly), wherein the distance that the radiation dose laterallyextends in a substantially uniform manner is up to about 0.75 mm away.In some embodiments the radiation dose extends away from the target inall directions (e.g., laterally, forwardly), wherein the distance thatthe radiation dose laterally extends in a substantially uniform manneris up to about 1.5 mm away. In some embodiments the radiation doseextends away from the target in all directions (e.g., laterally,forwardly), wherein the distance that the radiation dose laterallyextends in a substantially uniform manner is up to about 2.5 mm away.

In some embodiments, the radiation dose at a distance of 2 mm laterallyfrom the center of the target is less than 60% of the radiation dose onthe central axis of the target. In some embodiments, the radiation doseat a distance of 3 mm laterally from the center of the target is lessthan 25% of the radiation dose at the center of the target. In someembodiments, the radiation dose at a distance of 4 mm laterally from thecenter of the target is less than 10% of the radiation dose at thecenter of the target. Because the edge of the optic nerve is close tothe target, this dose profile provides greater safety for the opticnerve than methods of the prior art.

In some embodiments, the radiation dose is substantially uniform withina distance of up to about 1.0 mm (as measured laterally) from the centerof the target. In some embodiments, the radiation dose declines suchthat at a distance of about 2.0 mm (as measured laterally) from thecenter of the target, the radiation dose is less than about 25% of theradiation dose at the center of the target. In some embodiments, theradiation dose declines such that at a distance of about 2.5 mm (asmeasured laterally) from the center of the target, the radiation dose isless than about 10% of the radiation dose at the center of the target.

In some embodiments, the radiation dose is substantially uniform withina distance of up to about 6.0 mm (as measured laterally) from the centerof the target. In some embodiments, the radiation dose declines suchthat at a distance of about 12.0 mm (as measured laterally) from thecenter of the target, the radiation dose is less than about 25% of theradiation dose at the center of the target. In some embodiments, theradiation dose declines such that at a distance of about 15.0 mm (asmeasured laterally) from the center of the target, the radiation dose isless than about 10% of the radiation dose at the center of the target.

In some embodiments, the radiation dose is substantially uniform withina distance of up to about 10.0 mm (as measured laterally) from thecenter of the target. In some embodiments, the radiation dose declinessuch that at a distance of about 20.0 mm (as measured laterally) fromthe center of the target, the radiation dose is less than about 25% ofthe radiation dose at the center of the target. In some embodiments, theradiation dose declines such that at a distance of about 25.0 mm (asmeasured laterally) from the center of the target, the radiation dose isless than about 10% of the radiation dose at the center of the target.

In some embodiments, the radiation dose at the center of the target(e.g., radiation dose at the center of the choroidal neovascularmembrane) does not extend laterally to the entire macula (a diameter ofabout 1.5 mm to 6.0 mm). In some embodiments, the devices of the presentinvention may also treat a larger area and still have a faster radiationdose fall off as compared to devices of the prior art.

Benefit of Short Delivery Time

Without wishing to limit the present invention to any theory ormechanism, it is believed that faster delivery time of radiation isadvantageous because it allows the physician to hold the instrument inthe desired location with minimal fatigue, and it minimizes the amountof time that the patient is subjected to the procedure. Lower dose ratesand longer delivery times may cause fatigue in the physician, possiblyleading to the accidental movement of the cannula from the target.Furthermore, longer delivery times increase the chance of any movementsof the physician's hand or the patient's eye or head (when localanesthesia is employed, the patient is awake during the procedure).

Another benefit of a faster delivery time is the ability to employshort-term local anesthetics (e.g., lidocaine) and/or systemic inductiondrugs or sedatives (e.g., methohexital sodium, midazolam). Use ofshort-term anesthetics result in a quicker recovery of function (e.g.,motility, vision) after the procedure. Shorter acting anesthetics causeshorter-lasting respiratory depression in case of accidental centralnervous system injection.

Shutter System

In some embodiments, the cannula 100 comprises a shutter system disposednear or at the tip 200 of the cannula 100. The shutter system may besimilar to the shutter system of a camera. In some embodiments, ashutter system is used to deliver up to about a 200,000 Gy/min dose ratein a time frame of about 0.01 second. Without wishing to limit thepresent invention to any theory or mechanism, it is believed that ashutter system would be advantageous because it would allow for such ashort exposure time that the radiation dose can be delivered to thetarget without worry of a hand, eye, or head movement moving the cannula100 away from the target.

Alternatively to a shutter system, in some embodiments, a high dose ratecan be delivered in a short amount of time using a mechanism of a veryfast after-loaded system, wherein the RBS is quickly moved to thetreatment position for a quick dwell time and the retracted away fromthe treatment position.

The present invention is illustrated herein by example, and variousmodifications may be made by a person of ordinary skill in the art. Forexample, although the cannulae 100 of the present invention have beendescribed above in connection with the preferred sub-Tenon radiationdelivery generally above the macula, the cannulae 100 may be used todeliver radiation directly on the outer surface of the sclera 235, belowthe Tenon's capsule 230, and generally above portions of the retinaother than the macula. Moreover, in some embodiments, the devices (e.g.,cannulae 100) of the present invention may be used to deliver radiationfrom below the conjunctiva and above the Tenon's capsule 230. In someembodiments, the devices may be used to deliver radiation to theanterior half of the eye. In some embodiments, the devices may be usedto deliver radiation from above the conjunctiva. As another example, thearc length and/or radius of curvature of the distal portions of thecannulae may be modified to deliver radiation within the Tenon's capsule230 or the sclera 235, generally above the macula or other portions ofthe retina, if desired.

Additional Rationale of Device and Methods

Without wishing to limit the present invention to any theory ormechanism, it is believed that the methods of the present invention,which feature a posterior radiation approach, are superior to methodsthat employ either a pre-retinal approach or an intravitreal radiationapproach using an intravitreal device 910 (see FIG. 9, see U.S. Pat. No.7,223,225 B2) for several reasons.

For example, the pre-retinal approach (e.g., irradiating the target areaby directing the radiation from the anterior side of the retina backtoward the target) irradiates the anterior structures of the eye (e.g.,cornea, iris, ciliary body, lens) and has the potential to irradiate thetissues deeper than the lesion, such as the periorbital fat, bone, andthe brain. The intravitreal radiation approach (e.g., irradiating thetarget area by directing the radiation from within the vitreous chamberfrom the anterior side of the eye back towards the target) also has thepotential to irradiate the tissues deeper than the lesion (e.g.,periorbital fat, bone, brain) and also, in a forward direction, thelens, ciliary body and cornea. It is believed that the methods of thepresent invention will spare the patient from receiving ionizingradiation in the tissues behind the eye and deeper than the eye.According to the present invention, the radiation is directed forward(e.g., the radiation is directed from the posterior side of the eyeforward to the target) and is shielded in the back, and therefore excessradiation would enter primarily into the vitreous gel and avoid thesurrounding tissues (e.g., fat, bone, brain).

Keeping the cannula 100 in a fixed location and at a distance from thetarget during the treatment reduces the likelihood of errors andincreases the predictability of dose delivery. Conversely, approachingthe radiation treatment by inserting a device into the vitreous chamber(e.g., an intravitreal approach) requires a physician to hold the devicein a fixed location and a fixed distance from the target in the spaciousvitreous chamber (see FIG. 9). It may be difficult for the physician tohold precisely that position for any length of time. Furthermore, it isgenerally not possible for the physician/surgeon to know the exactdistance between the probe and the retina; he/she can only estimate thedistance. By approaching the treatment from behind the eye, thephysician is able to hold the device at a precise fixed distance fromthe target because the intervening structures (e.g., the sclera 235)support the device, help to hold the cannula 100 in place, and act as afixed spacer. This improves both the geometric accuracy and doseprecision. As shown in FIG. 29, Table 4, the radiation dose variesgreatly depending on the depth (e.g., distance away from the source asmeasured along line IR). For example, if the distance between the RBS(e.g., probe) is moved from 0.1 mm away from the target to 0.5 mm, thedose may decrease by about 25 to 50%.

The posterior approach is also easier and faster than the intravitrealapproach. The posterior approach is less invasive than the intravitrealapproach, and avoids the side effects of intravitreal procedures (e.g.,vitrectomy, intravitreal steroid injections or VEGF injections) whichare often cataractogenic, as well as the possibility of mechanicaltrauma to the retina or intraocular infection. The posterior approach issafer for the patient.

Without wishing to limit the present invention to any theory ormechanism, it is believed that the devices of the present invention areadvantageous over other posterior radiation devices of the prior artbecause the devices of the present invention are simpler mechanicallyand less prone to malfunction. In some embodiments, the devices of thepresent invention are only used one time.

Without wishing to limit the present invention to any theory ormechanism, it is believed that the unique radiation profile of thepresent invention is advantageous over the prior art. As discussedpreviously and as shown in FIG. 8, the devices and methods of thepresent invention, which suitably employ the rotationally symmetricalsurface concept described above, provide for a more sharply demarcateddose radiation profile from the edge of a substantially uniform doseregion. Other posterior devices do not provide this unique radiationprofile. The devices and methods of the present invention areadvantageous because they will deliver a therapeutic dose of radiationto the target (e.g., neovascular growths affecting the central maculastructures) while allowing for the radiation dose to fall off morequickly than the prior art, which helps prevent exposure of the opticnerve and/or the lens to radiation. Further, a faster fall off of thelateral radiation dose minimizes the risk and the extent of radiationretinopathy, retinitis, vasculitis, arterial and/or venous thrombosis,optic neuropathy and possibly hyatrogenic neoplasias.

In some embodiments, the cannula 100 is after-loaded with radiation. Insome embodiments, the RBS is pushed forward to an orifice 500 or awindow 510 at the tip 200 of the cannula 100. In some embodiments, thedevices of the present invention do not comprise a removable shield or ashutter.

The present methods of treatment may be used alone or in combinationwith a pharmaceutical, e.g., for treating Wet Age-Related MacularDegeneration. Non-limiting examples of pharmaceuticals that may be usedin combination with the present invention includes a radiationsensitizer an anti-VEGF (vascular endothelial growth factor) drug suchas Lucentis®, or Avastin®, and/or other synergistic drugs such assteroids, vascular disrupting agent therapies, and other anti-angiogenictherapies both pharmacologic and device-based.

For example, the present invention may be used in combination with apharmaceutical (e.g., a “first treatment”) such as an anti-angiogenesistreatment for inhibiting an angiogenesis target. The present inventionmay also be used in combination with more than one pharmaceutical (e.g.,a first treatment and a second treatment, etc.). Administration may besimultaneous or consecutive. For example, in some embodiments, thepresent invention is used in combination with an anti-angiogenesistreatment (e.g., the first treatment) and a steroid treatment (e.g., thesecond treatment), e.g., corticosteroid treatment.

Without wishing to limit the present invention to any theory ormechanism, non-limiting examples of angiogeneis inhibitors may includeangiopoeitin 2, soluble vascular endothelial growth factor receptor-1(VEGFR-1), soluble Tie2, soluble neuropilin-1 (NRP-1), endostatin,angiostatin, tissue inhibitor of metalloprotease-3 (TIMP-3), prolactin,platelet factor-4, calreticulin, thrombospondin 1 (TSP-1),thrombospondin 2 (TSP-1), Vandetanib (e.g., ZD6474), PDGF inhibitors,pigment epithelium-derived factor (PEDF), VEGF inhibitory aptamers,e.g., Macugen® (pegaptanib, Pfizer), antibodies or fragments thereof,e.g., anti-VEGF antibodies, e.g., bevacizumab (Avastin®, Genentech), orfragments thereof, e.g., ranibizumab (Lucentis®, Genentech), solublefins-like tyrosine kinase 1 (sFltl) polypeptides or polynucleotides;PTK/ZK; KRN633; inhibitors of integrins (e.g., αvβ3 and α5βl);VEGF-Trap® (Regeneron); Alpha2-antiplasmin, cartilage-derivedangiogenesis inhibitor (CDAI), disintegrin and metalloproteinase withthrombospondin motifs 1 (ADAMTS1), ADAMTS2, IFN-alpha, IFN-beta,IFN-gamma, chemokin (C-X-C motif) ligand 10 (CYCL10), IL-4, IL-12,IL-18, prothrombin, antithrombin III fragments, and vascular endothelialgrowth inhibitor (VEGI), anti-hypoxia inducible factor-1 (anti-HIF-1)compounds or treatments, and immunosuppressant compounds such ascalcineurin inhibitors (e.g., tacrolimus) or mTOR inhibitors (e.g.,rapamycin). e.g., see W.O. Pat. Application No. 2008/119500, thedisclosure of which is incorporated in its entirety by reference herein.

Without wishing to limit the present invention to any theory ormechanism, other angiogenesis inhibitors may also be found in U.S.Patent Application No. 2008/0193499; U.S. Pat. No. 7,091,175, U.S.Patent Application 2001/0041744; U.S. Pat. No. 6,472,379; U.S. Pat.Application No. 2002/0001630; U.S. Patent Application 2005/0043220; U.S.Patent Application 2004/0048807, the disclosures of which reincorporated in their entirety by reference herein.

Without wishing to limit the present invention to any theory ormechanism, non limiting examples of corticosteroids are 1′-alpha,17-alpha, 21-trihydroxypregn-4-ene-3,20-dione; 11-beta, 16-alpha,17,21-tetrahydroxypregn-4-ene-3,20-dione; 11-beta, 16-alpha,17,21-tetrahydroxypregn-1,4-diene-3,20-dione; 11-beta, 17-alpha,21-trihydroxy-6-alpha-methylpregn-4-ene-3,20-dione;11-dehydrocorticosterone; 11-deoxycortisol;11-hydroxy-1,4-androstadiene-3,17-dione; 11-ketotestosterone;14-hydroxyandrost-4-ene-3,6,17-trione; 15,17-dihydroxyprogesterone;16-methylhydrocortisone;17,21-dihydroxy-16-alpha-methylpregna-1,4,9(11)-triene-3,20-dione;17-alpha-hydroxypregn-4-ene-3,20-dione; 17-alpha-hydroxypregnenolone;17-hydroxy-16-beta-methyl-5-beta-pregn-9(11)-ene-3,20-dione;17-hydroxy-4,6,8(14)-pregnatriene-3,20-dione;17-hydroxypregna-4,9(11)-di-ene-3,20-dione; 18-hydroxycorticosterone;18-hydroxycortisone; 18-oxocortisol; 21-acetoxypregnenolone;21-deoxyaldosterone; 21-deoxycortisone; 2-deoxyecdysone;2-methylcortisone; 3-dehydroecdysone; 4-pregnene-17-alpha, 20-beta,21-triol-3,11-dione; 6,17,20-trihydroxypregn-4-ene-3-one;6-alpha-hydroxycortisol; 6-alpha-fluoroprednisolone,6-alpha-methylprednisolone, 6-alpha-methylprednisolone 21-acetate,6-alpha-methylprednisolone 21-hemisuccinate sodium salt,6-beta-hydroxycortisol, 6-alpha, 9-alpha-difluoroprednisolone 21-acetate17-butyrate, 6-hydroxycorticosterone; 6-hydroxydexamethasone;6-hydroxyprednisolone; 9-fluorocortisone; alclomethasone dipropionate;aldosterone; algestone; alphaderm; amadinone; amcinonide; anagestone;androstenedione; anecortave acetate; beclomethasone; beclomethasonedipropionate; betamethasone 17-valerate; betamethasone sodium acetate;betamethasone sodium phosphate; betamethasone valerate; bolasterone;budesonide; calusterone; chlormadinone; chloroprednisone;chloroprednisone acetate; cholesterol; ciclesonide; clobetasol;clobetasol propionate; clobetasone; clocortolone; clocortolone pivalate;clogestone; cloprednol; corticosterone; Cortisol; Cortisol acetate;Cortisol butyrate; Cortisol cypionate; Cortisol octanoate; Cortisolsodium phosphate; Cortisol sodium succinate; Cortisol valerate;cortisone; cortisone acetate; cortivazol; cortodoxone; daturaolone;deflazacort, 21-deoxycortisol, dehydroepiandrosterone; delmadinone;deoxycorticosterone; deprodone: descinolone; desonide; desoximethasone;dexafen; dexamethasone; dexamethasone 21-acetate; dexamethasone acetate;dexamethasone sodium phosphate; dichlorisone; diflorasone; diflorasonediacetate; diflucortolone; difluprednate; dihydroelatencin a;domoprednate; doxibetasol; ecdysone; ecdysterone; emoxolone; endrysone;enoxolone; fluazacort; flucinolone; flucloronide; fludrocortisone;fludrocortisone acetate; flugestone; flumethasone; flumethasonepivalate; flumoxonide; flunisolide; fluocinolone; fluocinoloneacetonide; fluocinonide; fluocortin butyl; 9-fluorocortisone;fluocortolone fluorohydroxyandrostenedione; fluorometholone;fluorometholone acetate; fluoxymesterone; fluperolone acetate;fluprednidene; fluprednisolone; flurandrenolide; fluticasone;fluticasone propionate; formebolone; formestane; formocortal;gestonorone; glyderinine; halcinonide; halobetasol propionate;halometasone; halopredone; haloprogesterone; hydrocortamate;hydrocortiosone cypionate; hydrocortisone; hydrocortisone 21-butyrate;hydrocortisone aceponate; hydrocortisone acetate; hydrocortisonebμteprate; hydrocortisone butyrate; hydrocortisone cypionate;hydrocortisone hemisuccinate; hydrocortisone probutate; hydrocortisonesodium phosphate; hydrocortisone sodium succinate; hydrocortisonevalerate; hydroxyprogesterone; inokosterone; isoflupredone;isoflupredone acetate; isoprednidene; loteprednol etabonate;meclorisone; mecortolon; medrogestone; medroxyprogesterone; medrysone;megestrol; megestrol acetate; melengestrol; meprednisone;methandrostenolone; methylprednisolone; methylprednisolone aceponate;methylprednisolone acetate; methylprednisolone hemisuccinate;methylprednisolone sodium succinate; methyltestosterone; metribolone;mometasone; mometasone furoate; mometasone furoate monohydrate; nisone;nomegestrol; norgestomet; norvinisterone; oxymesterone; paramethasone;paramethasone acetate; ponasterone; prednicarbate; prednisolamate;prednisolone; prednisolone 21-diethylaminoacetate; prednisolone21-hemisuccinate; prednisolone acetate; prednisolone farnesylate;prednisolone hemisuccinate; prednisolone-21 (beta-D-glucuronide);prednisolone metasulphobenzoate; prednisolone sodium phosphate;prednisolone steaglate; prednisolone tebutate; prednisolonetetrahydrophthalate; prednisone; prednival; prednylidene; pregnenolone;procinonide; tralonide; progesterone; promegestone; rhapontisterone;rimexolone; roxibolone; rubrosterone; stizophyllin; tixocortol;topterone; triamcinolone; triamcinolone acetonide; triamcinoloneacetonide 21-palmitate; triamcinolone benetonide; triamcinolonediacetate; triamcinolone hexacetonide; trimegestone; turkesterone; andwortmannin.

The terms “compound that inhibits VEGF,” “anti-VEGF treatment,” and/or“anti-VEGF drug” may refer to a compound (or the like) that inhibits theactivity or production of vascular endothelial growth factor (VEGF). Forexample, the terms may refer to compounds capable of binding VEGF,including small organic molecules, antibodies or antibody fragmentsspecific to VEGF, peptides, cyclic peptides, nucleic acids, antisensenucleic acids, RNAi, and ribozymes that inhibit VEGF expression at thenucleic acid level. Non-limiting examples of compounds that inhibit VEGFare nucleic acid ligands of VEGF (e.g., such as those described in U.S.Pat. No. 6,168,778 or U.S. Pat. No. 6,147,204), EYEOOI (previouslyreferred to as NX1838) which is a modified pegylated aptamer that bindswith high affinity to the major soluble human VEGF isoform; VEGFpolypeptides (e.g., U.S. Pat. No. 6,270,933 and WO Pat. No. 99/47677);oligonucleotides that inhibit VEGF expression at the nucleic acid level,for example antisense RNAs (e.g. U.S. Pat. No. 5,710,136; U.S. Pat. No.5,661,135; U.S. Pat. No. 5,641,756; U.S. Pat. No. 5,639,872; U.S. Pat.No. 5,639,736). Other examples of inhibitors of VEGF signaling known inthe art may include, e.g., ZD6474; COX-2, Tie2 receptor, angiopoietin,and neuropilin inhibitors; PEDF, endostatin, and angiostatin, solublefins-like tyrosine kinase 1 (sFltl) polypeptides or polynucleotides;PTK787/ZK222 584; KRN633; VEGF-Trap® (Regeneron); andAlpha2-antiplasmin. Compounds that inhibit VEGF may be antibodies to, orantibody fragments thereof, or aptamers of VEGF or a related familymember such as (VEGF B. I C. D; PDGF). Examples are anti-VEGFantibodies, e.g., Avastin™ (also reviewed as bevacizumab, Genentech), orfragments thereof, e.g., Lucentis™ (also reviewed as rhuFAb V2 orAMD-Fab; ranibizumab, Genentech), and other anti-VEGF compounds such asVEGF inhibitory aptamers, e.g., Macugen™ (also reviewed as pegaptanibsodium, anti-VEGF aptamer or EYEOOI, Pfizer). In some embodiments, acompound that inhibits VEGF can further be an immunosuppressant compound(e.g., calcineurin inhibitors, mTOR inhibitors). The disclosures of allreferenced U.S. patents and W.O patents are incorporated in theirentirety by reference herein.

In some embodiments, the pharmaceutical (e.g., angiogenesis inhibitor,e.g., VEGF-inhibitor, etc.) may comprise a compound selected from thegroup consisting of an oestrogen (e.g. oestrodiol), an androgen (e.g.testosterone) retinoic acid derivatives (e.g. 9-cis-retinoic acid,13-trans-retinoic acid, all-trans retinoic acid), a vitamin D derivative(e.g. calcipotriol, calcipotriene), a non-steroidal antiinflammatoryagent, a selective serotonin reuptake inhibitor (SSRI; e.g. fluoxetine,sertraline, paroxetine), a tricyclic antidepressant (TCA; e.g.maprotiline, amoxapine), a phenoxy phenol (e.g. triclosan), anantihistaminine (e.g. loratadine, epinastine), a phosphodiesteraseinhibitor (e.g. ibudilast), an anti-infective agent, a protein kinase Cinhibitor, a MAP kinase inhibitor, an anti-apoptotic agent, a growthfactor, a nutrient vitamin, an unsaturated fatty acid, and/or ocularanti-infective agents, for the treatment of the ophthalmic disorders setforth herein (see for example compounds disclosed in US 2003/0119786; WO2004/073614: WO 2005/051293; US 2004/0220153; WO 2005/027839; WO2005/037203; WO 03/0060026). Anti-infective agents may include but arenot limited to penicillins (ampicillin, aziocillin, carbenicillin,dicloxacillin, methicillin, nafcillin, oxacillin, penicillin G,piperacillin, and ticarcillin), cephalosporins (cefamandole, cefazolin,cefotaxime, cefsulodin, ceftazidime, ceftriaxone, cephalothin, andmoxalactam), aminoglycosides (amikacin, gentamicin, netilmicin,tobramycin, and neomycin), miscellaneous agents such as aztreonam,bacitracin, ciprofloxacin, clindamycin, chloramphenicol, cotrimoxazole,fusidic acid, imipenem, metronidazole, teicoplanin, and vancomycin),antifungals (amphotericin B, clotrimazole, econazole, fluconazole,flucytosine, itraconazole, ketoconazole, miconazole, natamycin,oxiconazole, and terconazole), antivirals (acyclovir, ethyldeoxyuridine,foscarnet, ganciclovir, idoxuridine, trifluridine, vidarabine, and(S)-1-(3-dydroxy-2-phospho-nyluethoxypropyl) cytosine (HPMPC)),antineoplastic agents (cell cycle (phase) nonspecific agents such asalkylating agents (chlorambucil, cyclophosphamide, mechlorethamine,melphalan, and busulfan), anthracycline antibiotics (doxorubicin,daunomycin, and dactinomycin), cisplatin, and nitrosoureas),antimetabolites such as antipyrimidines (cytarabine, fluorouracil andazacytidine), antifolates (methotrexate), antipurines (mercaptopurineand thioguanine), bleomycin, vinca alkaloids (vincrisine andvinblastine), podophylotoxins (etoposide (VP-16)), and nitrosoureas(carmustine, (BCNU)), and inhibitors of proteolytic enzymes such asplasminogen activator inhibitors.

The pharmaceutical (or combination of pharmaceuticals) may include ananti-paracyte (e.g., a paracyte is a cell that adheres and matures newvessels). The pharmaceutical (or combination of pharmaceuticals) mayinclude a VEGF-Trap (Bayer). The pharmaceutical (or combination ofpharmaceuticals) may comprise a PDT agent, e.g., verteporfin (Visudyne.Novartis), SnET2 PDT (Photrex, Miravant); a steroid, e.g. anecoratve(Retaane Depot, Alcon), dexamethasone (Posurdex, Allergan), floucinoloneacetonide (Iluvien, Alimera Sciences/pSivida); a microtubulede-stabilizer/VDA, e.g., CA4P (Zybresta, OXiGENE); a PEGylated anti-VEGFaptamer, e.g., pegaptanib (Macugen, OSI/Pfizer/Gilead Sciences); aPan-VEGF Fab′, e.g., ranulizumab (Lucentis, Genentech/Novartis);bevacizumab (Avastin. Genentech); a small molecule VEGFR inhibitor,e.g., AG-13958 (Pfizer); VEGF-Trap (Regeneron/Bayer); a soluble decoyfusion protein comprising portions of VEGFR1 and VEGFR2 that binds VEGFand PIGF, e.g., AVE0005 (Aflibercept (Regeneron/Sanofi); an RNAi, e.g.,Sima-027 (Merck/Allergan), ALN-VEG01 (Alnylam); an anti-a5B1 integrinFab′, e.g., F200 (Protein Design Lab); ACZ885F (Novartis); ananti-angiogenic compound, e.g., ATG-3/ATG-003 (CoMentis), an NSAID,e.g., xibrom bromfenac (Ista Pharmaceuticals Inc & Senju PharmaceuticalCo.); a small molecule resolvin, e.g., NPDI (Resolvyx); RX 10001 (RvEI);RX 10008; an immunosuppressive, anti-angiogenic, anti-migratory,anti-proliferative, anti-fibrotic, and/or anti-permeability compound,e.g. sirolimus (e.g., rapamycin) DE-109 (Santen & MacuSight); a siRNA,e.g., bevasiranib (OPKO Health Inc); an antibody fragment, e.g., ESBA903(ESBATech); a complement inhibitor, e.g., POT-4 (Potentia); a fusionprotein (consisting of a complement receptor 2 (CR2) fragment linked toan inhibitory domain of complement factor H(CFH) that inhibits thecomplement alternative pathway). e.g., TT30 (Taligen); analpha(5)beta(1) integrin, e.g., JSM-6427; a monoclonal antibody (againstsphingosine 1-phosphate), e.g., sphingomab (Lpath Inc.); squalamine; ananti-PDGF aptamer against PDGF-B, e.g., E10030 (Ophthotech); an anti-C5aptamer, e.g., ARC1905 (Ophthotech); a stem cell based therapy. e.g.,HuCNS-SC (StemCells Inc); pyrimidine derivatives, benzodiazepinylderivatives; embryonic stem cell therapies: aminoacyl tRNA synthetasefragments; PDGF anti-cancer drugs in combination with Lucentis (e.g.,Gleeve tablet+Lucentis); amino acid peptide isolated from scorpion venom(e.g., TM601, chlorotoxin, TransMolecular Inc); RetinoStat (OxfordBioScience/Sanofi Aventis); RetinoStat (Oxford BioMedica); adPEDF(GenVec); adenoviral PEDG gene therapy, protein therapeutics, moleculardiagnostics; stem cells; non-steroidal inhibior of CREB regulatedtranscription coactivator-1 and TORC, e.g., Palomid 529 (P529) (PalomaPharmaceuticals); antibodies; Isonep; sustained release Lucentis;Macroesis (Buckeye); immunoconjugates (e.g., hi-con1, IconicTherapeutics); heterocomplex of VEGG linked to a keyhole limpethemocyanin (e.g., VEGF Kinoid, Neovacs); hESCs; microplasmin, e.g. MIVIS(ThromboGenics); compound regulating lipase gene; Medidur FA(pSivida/Alimera); a small interfering RNA product, e.g., RTP-801i-14(Pfizer/Quank/Silence Therapeutic); a siRNA targeting hypoxia-induciblegenes, e.g. RTP801 (Pfizer/Quark); PTK787; ACE-041 (Acceleron Pharma);rC3-1 (InaCode BioPharmaceutics, Inc.); ACU-4429 (Acucela); ACU-02(Acucela); a covalently-linked form of zinc monocysteine complex, e.g.,Zinthionein (Pipex, Adeona Pharmaceuticals); I-vation (SurModicsInc/Merck); phosphatase-activated tumor vascular targeting agent, e.g.,Zybrestat (Oxigene); retinylamine (Case Western University); TRC093 TRC105 (Tracon Pharmaceuticals); volociximab (Opthotech); E10030(Ophthotech); SAR 1118 (SARcode Corp); Intelligent Retinal ImplantSystem; RNAi drugs (Traversa, for example); PMX53 (Arana Therapeutics);SMT D004 (Summit Corpic); aptamer therapeutics (Archemix Corp); MC1101(MacuClear); infra-red light; iCo-007 (iCo Therapeutics); NT-501(Neurotech Pharmaceuticals); OT-551 (Othera Pharmaceuticals); VPC51299(Catena Pharmaceuticals); fenretinide (Sirion Therapeutics); ananti-angiogenic and/or angiolytic compount, e.g., Eye Drop (OcuCureTherapeutics); CCR3Marker (University of Kentucky); Alterase(Medlmmune/Calaylst Biosciences); iPS (Japan Kyoto University); CLT-003(Charlesson); OXY111A (NormOxys Inc.); a photosensitizer (e.g., Photrex,Miravant Medical Technologies); Visudyne with Triamcinolone (QLT);Bevasiranib with ranibizumab (Opko Health); VEGF Trap-Eye (Bayer andRegeneron); AGN745 (Allergan and Merck & Co.); Visudyne with Lucentis,Dexamethasone (QLT); Medidur FA with Lucentis (pSivida); Lucentis withVisudyne (Genentech); TG100801 (Targeted Genetics); ST602 (SirionTherapeutics) Neurosolve (Vitreoretinal Technologies); an NF-kBinhibitor (e.g., OT551, Othera Pharmaceuticals); DNA-damage-inducibletranscript 4 (DDIT4) inhibitor (e.g., RTP801i, Quark Pharmaceuticals andSilence Therapeutics); a C-Kit Receptor Tyrosine Kinase (CD117)Inhibitor (e.g., Armala, GlaxoSmithKline); a Ciliary Neutrophic GrowthFactor (CNTF) Receptor Agonist (e.g., NT501, Neurotech); an Alpha7Non-Neuronal Nicotinic Receptor Antagonist (e.g., ATG003, CoMentis); aslow-released corticosteroid (e.g., Iluvien, Alimera); aSphingosine-1-Phosphate (S1P) Receptor Antagonist (e.g., Isonep, Lpath);a polyamine analogue (e.g., PG11047, Progen Pharmaceuticals); E10030with Lucentis (Ophthotech); pigment epithelial derived GF, e.g., AdPEDF(GenVec); an mTOR inhibitor, e.g., Sirolimus (MacuSight); a Non-retinoidvisual cycle modulator, e.g., ACU4429 (Otsuka Pharmaceutical/Acucela); aC5 Complement Inhibitor NEGF-A Inhibitor, e.g., ARC1905 with Lucentis(Ophthotech); an antisense insulin receptor Substrate 1 (IRS-1), e.g.,GS101 (Gene Signal); an alpha(5)beta(1) integrin receptor agonist, e.g.,SB267268 (GlaxoSmithKline), Volociximab (Biogen Idec and PDL BioPharma);JSM6427 (Jerini/PR Pharmaceuticals).

The pharmaceutical (or combination of pharmaceuticals) may furthercomprise a pharmaceutically acceptable carrier. Such pharmaceuticalcarriers are well known to one of ordinary skill in the art. In someembodiments, the pharmaceutical (or combination of pharmaceuticals) maybe administered as a slow-release formulation. Such slow-releaseformulations are well known to one of ordinary skill in the art, forexample the pharmaceutical may be in the form of a vehicle such as amicro-capsule or matrix of biocompatible polymers such aspolycaprolactone, polyglycolic acid, polylactic acid, polyanhydrides,polylactide-co-glycolides, polyamino acids, polyethylene oxide, acrylicterminated polyethylene oxide, polyamides, polyethylenes,polyacrylonitriles, polyphosphazenes, poly(ortho esters), sucroseacetate isobutyrate (SAIB), and other polymers such as those disclosedin U.S. Pat. Nos. 6,667,371; 6,613,355; 6,596.296; 6,413,536; 5,968,543;4,079,038; 4,093,709; 4,131,648; 4,138,344; 4,180,646; 4,304,767;4,946,931, or lipids that may be formulated as microspheres orliposomes. The formulation and loading of microspheres, microcapsules,liposomes, etc. are standard techniques known by one skilled in the art.

Cannulas for Administration of Pharmaceuticals in Combination with RBS

The cannula may deliver both the RBA and at least one pharmaceutical(e.g., as described above). Administration may be simultaneous orconsecutive. The pharmaceuticals may be housed in a chamber 710 (ormultiple chambers) disposed in the cannula, for example in the proximalportion, in the handle 140, in the radiation shielding pig, etc. (seeFIG. 23). Or, the chamber may alternatively be disposed in the distalportion (e.g., in a “distal pharmaceutical chamber”). In someembodiments, the cannula comprises a first chamber 710 for housing afirst pharmaceutical (see FIG. 23). In some embodiments, the cannulacomprises a first chamber 710 for housing a first pharmaceutical and asecond chamber (e.g., 712) for housing a second pharmaceutical (see FIG.23A). In some embodiments, the cannula comprises a first chamber 710 forhousing a first pharmaceutical, a second chamber (e.g., 712) for housinga second pharmaceutical, and a third chamber for housing a thirdpharmaceutical.

In some embodiments, the chamber(s) 710 in the cannula are pre-loadedwith a fixed volume of the pharmaceutical(s). In some embodiments, thechamber(s) 710 comprise an opening for providing access to thechamber(s) 710, for example for loading the chamber(s) 710 with thepharmaceutical(s). A closing mechanism may be disposed on the opening,wherein the closing mechanism can move between an open position and aclosed position for respectively allowing and preventing access to thechamber 710 (e.g., preventing leaking of the pharmaceutical).

The cannula may comprise one or more pharmaceutical orifices 730 fordispensing the pharmaceutical. The pharmaceutical orifice 730 may bedisposed on the distal portion 110, for example at or near the tip (seeFIG. 24). The pharmaceutical orifice 730 may be disposed adjacent to thetreatment position of the RBS.

The chamber(s) 710 housing the pharmaceutical(s) are fluidly connectedto one or more pharmaceutical orifices 730. For example, in someembodiments, the first chamber 710 is fluidly connected to a firstpharmaceutical orifice 730. In some embodiments, the first chamber 710is fluidly connected to a first pharmaceutical orifice 730 and thesecond chamber is also fluidly connected to the first pharmaceuticalorifice 730. In some embodiments, the first chamber 710 is fluidlyconnected to a first pharmaceutical orifice 730 and the second chamberis fluidly connected to a second pharmaceutical orifice. The chamber(s)710 housing the pharmaceutical(s) may be fluidly connected to thepharmaceutical orifice 730 via a tube 720. The tube 720 may, forexample, be a part of the means of advancing the RBS, e.g., guide wire350, ribbon, memory wire, etc (e.g., see FIG. 24A). Or, the tube 720 maybe separate from the means of advancing the RBS (see FIG. 23), e.g., theguide wire 250, ribbon, memory wire, etc.

The cannula comprises one or more advancing mechanisms for advancing thepharmaceutical from the chamber(s) 710 to the pharmaceutical orifice(s)730, e.g. via the tube 720, and ultimately causing the dispensing of thepharmaceutical. The advancing mechanism may be incorporated into theproximal portion, for example in the handle 140. Non-limiting examplesof such mechanisms include pneumatic mechanism (e.g., air pressure), avacuum mechanism, a slide mechanism, a button mechanism, a dialmechanism, a thumb ring, a graduated dial, a slider, a fitting, aToughy-Burst type fitting, a plunger (e.g., a solid stick, a piston, ashaft, etc.), a hydrostatic pressure mechanism, the like, or acombination thereof. For example, a plunger mechanism may push thepharmaceutical (e.g., angiogenesis inhibitor) from the chamber to theorifice via the tube. As shown in FIG. 25, the plunger mechanism 760 maycomprise a means of advancing both the RBS and the pharmaceutical(s),for example the plunger mechanism 760 may comprise two plunger rings761, 762. The present invention is not limited to the examples ofadvancing means described herein, for example FIG. 25 is merely oneexample of many types of employable advancing means.

The pharmaceutical orifices 730 may be constructed in a variety ofshapes, for example shapes such as a circle, a square, an oval, arectangle, an ellipse, a triangle, or an irregular shape. In someembodiments, the pharmaceutical orifice 730 has an area of about 0.01mm² to about 0.1 mm². In some embodiments, the pharmaceutical orifice730 has an area of about 0.1 mm² to about 1.0 mm². In some embodiments,the pharmaceutical orifice 730 has an area of about 1.0 mm² to about10.0 mm².

In some embodiments, the distal edge of the pharmaceutical orifice 730is located between about 0.1 mm and 0.5 mm from the tip of the distalportion. In some embodiments, the distal edge of the pharmaceuticalorifice 730 is located between about 0.5 mm and 1.0 mm from the tip ofthe distal portion 110. In some embodiments, the distal edge of thepharmaceutical orifice 730 is located between about 1.0 mm and 2.0 mmfrom the tip of the distal portion 110. In some embodiments, the distaledge of the pharmaceutical orifice 730 is located between about 2.0 mmand 5.0 mm from the tip of the distal portion. In some embodiments, thedistal edge of the pharmaceutical orifice 730 is located between about5.0 mm and 10.0 mm from the tip of the distal portion 110. In someembodiments, the distal edge of the pharmaceutical orifice 730 islocated between about 10.0 mm and 20.0 mm from the tip of the distalportion.

Example 1 Surgical Technique

The following example describes a surgical procedure for use of thecannulae of the present invention. The eye is anesthetized with aperibulbar or retrobulbar injection of a short acting anesthetic (e.g.,Lydocaine). A button hole incision in the superotemporal conjunctiva ispreformed followed by a button hole incision of the underlying Tenoncapsule 230.

If a cannula 100 comprising a distal chamber 210 is used, a smallconjunctive peritomy (as large as the diameter of the distal chamber) isperformed at the superotemporal quadrant. A Tenon incision of the samesize is then performed in the same area to access the subtenon space.

Balanced salt solution and/or lydocaine is then injected in the subtenonspace to separate gently the Tenon capsule 230 from the sclera 235.

The cannula 100 is then inserted in the subtenon space and slid backuntil the tip 200 is at the posterior pole of the eye. In someembodiments, the cannula 100 comprises a locator 160. The locator 160indicates when the correct position has been reached. In someembodiments, the cannula 100 comprises a protuberance to act as anindentation tip 600. The surgeon may then observe the indentation tip600 or simply the indentation in the retina caused by the cannula 100using indirect opthalmoscopy through the dialated pupil. If theindentation indicates the radiotherapy is not exactly on the underlyingthe choroidal neovascular membrane, the surgeon may adjust the positionof the cannula 100 while directly visualizing the posterior pole with orwithout the aid of an operating microscope/ophthalmoscope (thisadjustment is the “fine positioning” adjustment). In some embodiments,the surgeon adjusts the position of the cannula while the patient's eyeis in a primary gaze position. In some embodiments, the surgeon adjuststhe position of the cannula while the patient's eye is in any one of thefollowing position: elevated, depressed, adducted, elevated andadducted, elevated and abducted, depressed and adducted, and depressedand abducted.

In some embodiments, the cannula 100 comprises a pilot light source 610near the tip 210 of the cannula 100 or along the length of the cannula100. The light may be seen through transillumination and may help guidethe surgeon to the correct positioning of the cannula 100. In someembodiments, the light source 610 is directed through the cannula 100 byfiberoptics or by placement of a LED.

In some embodiments, once the cannula 100 is in place, the RBS (e.g.,disk 405, seed-shaped RBS 400) is then pushed to the distal portion 110of the cannula 100. The radiation escapes the cannula 100 through anorifice 500 or a window 510 located on the side/bottom of the cannula100 adjacent to the sclera 235. In some embodiments, the distal end 320of the memory wire 300 comprises the RBS, and the radioactive portion ofthe memory wire 300 is pushed to the tip 200 of the distal portion 110of the cannula 100. In some embodiments, the memory wire 300 is pushedinto the distal chamber 210 or into a balloon.

The RBS (e.g., disk 405) is left in place for the desired length oftime. When the planned treatment time has elapsed, the RBS (e.g., disk405, memory wire 300) is then retracted to its original position. Thecannula 100 may then be removed from the subtenon space. The conjunctivamay then be simply reapproximated or closed with bipolar cautery or withone, two, or more interrupted reabsorbable sutures.

The button hole cunjunctiva/tenon incision has several advantages over atrue conjunctiva/Tenon incision. It is less invasive, faster, easier toclose, more likely to be amenable to simple reapproximation, less likelyto require sutures, and causes less conjunctiva scarring (which may beimportant if the patient has had or will have glaucoma surgery).

Example 2 Fast Radiation Fall Off at the Edge of the Target

After the cannula is placed into position, an RBS is introduced to thesclera region on the eye ball that corresponds with the target (e.g.,macula lesion) on the retina. Radionuclide of the RBS is Sr-90, and theRBS has a rotationally symmetrical exposure surface (e.g., circular)(see FIG. 14E). The exposure surface of the RBS has a diameter of about3 mm. The target is 3 mm in diameter and is about 1.5 mm away from theexposure surface of the RBS.

As shown in FIG. 22, a target that is 1.5 mm away from the exposuresurface has a radiation profile where the intensity of the radiation atthe edge falls off significantly, i.e., there is a fast fall of at thetarget edge. When a shielding (deep wall, see FIG. 21) is employed, theradiation fall off at the edge is faster compared to when there is noshielding.

In this example, the ratio of the target diameter to the exposuresurface diameter is about 1:1.

Various modifications of the invention, in addition to those describedherein, will be apparent to those skilled in the art from the foregoingdescription. Such modifications are also intended to fall within thescope of the appended claims. Each reference cited in the presentapplication is incorporated herein by reference in its entirety.

Although there has been shown and described the preferred embodiment ofthe present invention, it will be readily apparent to those skilled inthe art that modifications may be made thereto which do not exceed thescope of the appended claims. Therefore, the scope of the invention isonly to be limited by the following claims.

What is claimed is:
 1. A method of irradiating a target of an eye in apatient, said method comprising: (a) inserting a cannula into apotential space under a Tenon's capsule and above a sclera of the eye ofthe patient, the cannula configured to have a radionuclide brachytherapysource (RBS) at a treatment position, (b) observing through a pupil theposition of the treatment position in a posterior pole of the eye, (c)adjusting the cannula that is under the Tenon's capsule to achieve finepositioning of the treatment position, the fine positioning is achievedwhen the treatment position is over a target, (d) irradiating the targetwith the RBS.
 2. The method of claim 1, wherein the Tenon's capsuleguides insertion of the cannula and provides positioning support for thecannula.
 3. The method of claim 1, wherein the target is located on avitreous side of the eye.
 4. The method of claim 1, wherein the RBS isloaded into the cannula before the cannula is inserted.
 5. The method ofclaim 1, wherein the RBS is loaded into the cannula after the cannula isinserted.
 6. The method of claim 1, wherein the cannula is a fixed shapecannula.
 7. The method of claim 1, wherein the cannula is a flexiblecannula, including an endoscope.
 8. The method of claim 1, wherein thetarget is a lesion associated with a retina of the eye.
 9. The method ofclaim 8, wherein the lesion is a neovascular lesion.
 10. The method ofclaim 8, wherein the lesion is a benign growth or a malignant growth.11. The method of claim 1, wherein the RBS provides a dose rate ofbetween about 0.1 to 1 Gy/min to the target.
 12. The method of claim 1,wherein the RBS provides a dose rate of between about 1 to 10 Gy/min tothe target.
 13. The method of claim 1, wherein the RBS provides a doserate of between about 10 to 20 Gy/min to the target.
 14. The method ofclaim 1, wherein the RBS provides a dose rate of between about 20 to 30Gy/min to the target.
 15. The method of claim 1, wherein the RBSprovides a dose rate of between about 30 to 40 Gy/min to the target. 16.The method of claim 1, wherein the RBS provides a dose rate of betweenabout 40 to 50 Gy/min to the target.
 17. The method of claim 1, whereinthe RBS provides a dose rate of between about 50 to 75 Gy/min to thetarget.
 18. The method of claim 1, wherein the RBS provides a dose rateof between about 75 to 100 Gy/min to the target.
 19. A method ofirradiating a target of an eye in a patient, said method comprising: (a)inserting a cannula into a potential space under a Tenon's capsule andabove a sclera of the eye of the patient; (b) placing a distal portionof the cannula on or near a sclera behind the target; (c) observingthrough a pupil the position of the distal portion of the cannula in aposterior pole of the eye; (d) adjusting the cannula that is under theTenon's capsule to achieve fine positioning of the distal portion of thecannula, the fine positioning is achieved when a treatment position ofthe distal portion is positioned over a target, (e) advancing aradionuclide brachytherapy source (RBS) through the cannula to thetreatment position of the distal portion via a means for advancing aRBS; and (f) exposing the target to the RBS.
 20. A method of deliveringa radiation to an eye, said method comprising irradiating a target on avitreous side of the eye from an outer surface of a sclera via a cannulacomprising a radionuclide brachytherapy source (RBS) inserted underTenon's capsule, wherein the target receives a dose rate of greater thanabout 10 Gy/min, the method further comprises: (a) observing through apupil a position of a treatment position in a posterior pole of the eye,(b) adjusting the cannula that is under the Tenon's capsule to achievefine positioning of the treatment position, the fine positioning isachieved when the treatment position is over a target.